Aryl substituted indoles and the use thereof

ABSTRACT

The invention relates to aryl and heteroaryl substituted compounds of Formula (I), and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein G, R 1 , and Z 1 -Z 5  are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain.

BACKGROUND OF THE INVENTION Field of the Invention

This invention is in the field of medicinal chemistry. The inventionrelates to novel aryl and heteroaryl substituted compounds, andspecifically novel aryl substituted indolyl compounds, and the use ofthese compounds as blockers of sodium (Na⁺) channels.

Background Art

Voltage-gated sodium channels (VGSCs) are found in all excitable cells.In neuronal cells of the central nervous system (CNS) and peripheralnervous system (PNS) sodium channels are primarily responsible forgenerating the rapid upstroke of the action potential. In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper function of sodiumchannels is therefore necessary for normal function of the neuron.Consequently, aberrant sodium channel function is thought to underlie avariety of medical disorders (See Hubner et al., Hum. Mol. Genet.11:2435-2445 (2002) for a general review of inherited ion channeldisorders) including epilepsy (Yogeeswari et al, Curr. Drug Target5:589-602 (2004)), arrhythmia (Noble, Proc. Natl. Acad. Sci. USA99:5755-5756 (2002)), myotonia (Cannon, Kidney Int. 57:772-779 (2000)),and pain (Wood et al., J. Neurobiol., 61:55-71 (2004)).

VGSCs are composed of one α-subunit, that forms the core of the channeland is responsible for voltage-dependent gating and ion permeation, andseveral auxiliary β-subunits (see, e.g., Chahine et al., CNS &Neurological Disorders-Drug Targets 7:144-158 (2008) and Kyle and Ilyin,J. Med. Chem. 50:2583-2588 (2007)). α-Subunits are large proteinscomposed of four homologous domains. Each domain contains six α-helicaltransmembrane spanning segments. There are currently 9 known members ofthe family of voltage-gated sodium channel α-subunits. Names for thisfamily include SCNx, SCNAx, and Na_(v)x.x (see Table 1, below). The VGSCfamily has been phylogenetically divided into two subfamilies Na_(v)1.x(all but SCN6A) and Na_(v)2.x (SCN6A). The Na_(y)1.x subfamily can befunctionally subdivided into two groups, those which are sensitive toblocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which areresistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).

There are three members of the subgroup of TTX-resistant sodiumchannels. The SCN5A gene product (Na_(v)1.5, Hl) is almost exclusivelyexpressed in cardiac tissue and has been shown to underlie a variety ofcardiac arrhythmias and other conduction disorders (Liu et al., Am. J.Pharmacogenomics 3:173-179 (2003)). Consequently, blockers of Na_(v)1.5have found clinical utility in treatment of such disorders (Srivatsa etal., Curr. Cardiol. Rep. 4:401-410 (2002)). The remaining TTX-resistantsodium channels, Na_(v)1.8 (SCN10A, PN3, SNS) and Na_(v)1.9 (SCN11A,NaN, SNS2) are expressed in the peripheral nervous system and showpreferential expression in primary nociceptive neurons. Human geneticvariants of these channels have not been associated with any inheritedclinical disorder. However, aberrant expression of Na_(v)1.8 has beenfound in the CNS of human multiple sclerosis (MS) patients and also in arodent model of MS (Black et al., Proc. Natl. Acad Sci. USA97:11598-115602 (2000)). Evidence for involvement in nociception is bothassociative (preferential expression in nociceptive neurons) and direct(genetic knockout). Na_(v)1.8-null mice exhibited typical nociceptivebehavior in response to acute noxious stimulation but had significantdeficits in referred pain and hyperalgesia (Laird et al., J. Neurosci.22:8352-8356 (2002)).

TABLE 1 Voltage-gated sodium channel gene family Gene Tissue TTX IC₅₀Disease Type Symbol Distribution (nM) Association Indications Na_(v)1.1SCN1A CNS/PNS 10 Epilepsy Pain, seizures, neurodegeneration Na_(v)1.2SCN2A CNS 10 Epilepsy Epilepsy, neurodegeneration Na_(v)1.3 SCN3A CNS 15— Pain Na_(v)1.4 SCN4A Skeletal muscle 25 Myotonia Myotonia Na_(v)1.5SCN5A Heart muscle 2,000 Arrhythmia Arrhythmia Na_(v)1.6 SCN8A CNS/PNS 6— Pain, movement disorders Na_(v)1.7 SCN9A PNS 25 Erythermalgia PainNa_(v)1.8 SCN10A PNS 50,000 — Pain Na_(v)1.9 SCN11A PNS 1,000 — Pain

The Na_(v)1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows ˜90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA 94:1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 may play a keyrole in various pain states, including acute, inflammatory and/orneuropathic pain. Deletion of the SCN9A gene in nociceptive neurons ofmice led to an increase in mechanical and thermal pain thresholds andreduction or abolition of inflammatory pain responses (Nassar et al.,Proc Natl. Acad. Sci. USA 101:12706-12711 (2004)).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics, e.g., lidocaine and bupivacaine, and in the treatmentof cardiac arrhythmias, e.g., propafenone and amiodarone, and epilepsy,e.g., lamotrigine, phenytoin and carbamazepine (see Clare et al., DrugDiscovery Today 5:506-510 (2000); Lai et al., Annu. Rev. Pharmacol.Toxicol. 44:371-397 (2004); Anger et al., J. Med. Chem. 44:115-137(2001), and Catterall, Trends Pharmacol. Sci. 8:57-65 (1987)). Each ofthese agents is believed to act by interfering with the rapid influx ofsodium ions.

Other sodium channel blockers such as BW619C89 and lifarizine have beenshown to be neuroprotective in animal models of global and focalischemia (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994);Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).

It has also been reported that sodium channel-blocking agents may beuseful in the treatment of pain, including acute, chronic, inflammatory,neuropathic, and other types of pain such as rectal, ocular, andsubmandibular pain typically associated with paroxysmal extreme paindisorder; see, for example, Kyle and Ilyin, J. Med. Chem. 50:2583-2588(2007); Wood et al., J. Neurobiol. 61:55-71 (2004); Baker et al., TRENDSin Pharmacological Sciences 22:27-31 (2001); and Lai et al., CurrentOpinion in Neurobiology 13:291-297 (2003); the treament of neurologicaldisorders such as epilepsy, seizures, epilepsy with febrile seizures,epilepsy with benign familial neonatal infantile seizures, inheritedpain disorders, e.g., primary erthermalgia and paroxysmal extreme paindisorder, familial hemiplegic migraine, and movement disorder; and thetreatment of other psychiatric disorders such as autism, cerebelleratrophy, ataxia, and mental retardation; see, for example, Chahine etal., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) andMeisler and Kearney, J. Clin. Invest. 115:2010-2017 (2005). In additionto the above-mentioned clinical uses, carbamazepine, lidocaine andphenytoin are occasionally used to treat neuropathic pain, such as fromtrigeminal neuralgia, diabetic neuropathy and other forms of nervedamage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)).Furthermore, based on a number of similarities between chronic pain andtinnitus, (Moller, Am. J. Otol. 18:577-585 (1997); Tonndorf, Hear. Res.28:271-275 (1987)) it has been proposed that tinnitus should be viewedas a form of chronic pain sensation (Simpson, et al., Tip. 20:12-18(1999)). Indeed, lidocaine and carbamazepine have been shown to beefficacious in treating tinnitus (Majumdar, B. et al., Clin.Otolaryngol. 8:175-180 (1983); Donaldson, Laryngol. Otol. 95:947-951(1981)).

Many patients with either acute or chronic pain disorders respond poorlyto current pain therapies, and the development of resistance orinsensitivity to opiates is common. In addition, many of the currentlyavailable treatments have undesirable side effects.

In view of the limited efficacy and/or unacceptable side-effects of thecurrently available agents, there is a pressing need for more effectiveand safer analgesics that work by blocking sodium channels.

BRIEF SUMMARY OF THE INVENTION

The present invention is related to the use of compounds represented byFormula I, below, and the pharmaceutically acceptable salts, prodrugsand solvates thereof (collectively referred to herein as “Compounds ofthe Invention”), as blockers of sodium (Na⁺) channels.

The invention is also related to treating a disorder responsive to theblockade of sodium channels in a mammal suffering from excess activityof said channels by administering an effective amount of a Compound ofthe Invention as described herein.

Compounds useful in the present invention have not been heretoforereported. Thus, one aspect of the present invention is directed to novelcompounds of Formula I, as well as their pharmaceutically acceptablesalts, prodrugs and solvates.

Another aspect of the present invention is directed to the use of thenovel compounds of Formula I, and their pharmaceutically acceptablesalts, prodrugs and solvates, as modulators, in particular blockers ofsodium channels.

A further aspect of the present invention is to provide a method fortreating pain (e.g., acute pain, chronic pain, which includes but is notlimited to, neuropathic pain, postoperative pain and inflammatory pain,or surgical pain) by administering an effective amount of a Compound fothe Invention to a mammal in need of such treatment. Specifically, thepresent invention provides a method for preemptive or palliativetreatment of pain by administering an effective amount of a Compound ofthe Invention to a mammal in need of such treatment.

A further aspect of the present invention is to provide a method fortreating stroke, neuronal damage resulting from head trauma, epilepsy,seizures, general epilepsy with febrile seizures, severe myoclonicepilepsy in infancy, neuronal loss following global and focal ischemia,migraine, familial primary erythromelalgia, paroxysmal extreme paindisorder, cerebellar atrophy, ataxia, distonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, by administering an effectiveamount of a Compound of the Invention to a mammal in need of suchtreatment.

A further aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating a disorder responsive to the blockade ofsodium ion channels, said pharmaceutical composition containing aneffective amount of a Compound of the Invention in a mixture with one ormore pharmaceutically acceptable carriers.

Also, an aspect of the invention is to provide a method of modulating,preferably blocking sodium channels in a mammal, wherein said methodcomprises administering to the mammal an effective amount of at leastone Compound of the Invention.

A further aspect of the invention is to provide a Compound of theInvention for use in treating pain (e.g., acute pain, chronic pain,which includes but is not limited to, neuropathic pain, postoperativepain and inflammatory pain, or surgical pain) in a mammal.

A further aspect of the invention is to provide a Compound of theInvention for use in the treatment of stroke, neuronal damage resultingfrom head trauma, epilepsy, seizures, general epilepsy with febrileseizures, severe myoclonic epilepsy in infancy, neuronal loss followingglobal and focal ischemia, migraine, familial primary erythromelalgia,paroxysmal extreme pain disorder, cerebellar atrophy, ataxia, distonia,tremor, mental retardation, autism, a neurodegenerative disorder (e.g.,Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson'sdisease), manic depression, tinnitus, myotonia, a movement disorder, orcardiac arrhythmia, or providing local anesthesia in a mammal.

A further aspect of the present invention is to provide radiolabeledCompounds of the Invention and the use of such compounds as radioligandsin any appropriately selected competitive binding assays and screeningmethodologies. Thus, the invention further provides a method forscreening a candidate compound for its ability to bind to a sodiumchannel or a sodium channel subunit using a radiolabeled Compound of theInvention. In certain embodiments, the compound is radiolabeled with ³H,¹¹C, or ¹⁴C. This competitive binding assay can be conducted using anyappropriately selected methodology. In one embodiment, the screeningmethod comprises a) introducing a fixed concentration of theradiolabeled compound to an in vitro preparation comprising a soluble ormembrane-associated sodium channel, subunit or fragment under conditionsthat permit the radiolabeled compound to bind to the channel, subunit orfragment, respectively, to form a conjugate; b) titrating the mixturewith a candidate compound; and c) determining the ability of thecandidate compound to displace the radiolabeled compound from saidchannel, subunit or fragment.

A further aspect of the invention is to provide the use of a Compound ofthe Invention in the manufacture of a medicament for treating pain in amammal. In one embodiment, the invention provides the use of a Compoundof the Invention in the manufacture of a medicament for palliative orpreemptive treatment of pain, such as acute pain, chronic pain, orsurgical pain.

A further aspect of the invention is to provide the use of a Compound ofthe Invention in the manufacture of a medicament for treating stroke,neuronal damage resulting from head trauma, epilepsy, seizures, generalepilepsy with febrile seizures, severe myoclonic epilepsy in infancy,neuronal loss following global and focal ischemia, migraine, familialprimary erythromelalgia, paroxysmal extreme pain disorder, cerebellaratrophy, ataxia, distonia, tremor, mental retardation, autism, aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), manic depression,tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, orproviding local anesthesia in a mammal.

A further aspect of the invention is to provide compounds represented byFormula XX, below, and the pharmaceutically acceptable salts, prodrugsand solvates thereof, and a method of treating pain (e.g., acute pain,chronic pain, which includes but is not limited to, neuropathic pain,postoperative pain and inflammatory pain, or surgical pain), stroke,neuronal damage resulting from head trauma, epilepsy, seizures, generalepilepsy with febrile seizures, severe myoclonic epilepsy in infancy,neuronal loss following global and focal ischemia, migraine, familialprimary erythromelalgia, paroxysmal extreme pain disorder, cerebellaratrophy, ataxia, distonia, tremor, mental retardation, autism, aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), manic depression,tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, orproviding local anesthesia in a mammal by administering an effectiveamount of a compound of Formula XX, or a pharmaceutically acceptablesalt, prodrug, or solvate thereof, to a mammal in need thereof.

Additional embodiments and advantages of the invention will be set forthin part in the description that follows, and will flow from thedescription, or may be learned by practice of the invention. Theembodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention is based on the use of compounds ofFormula I, and the pharmaceutically acceptable salts, prodrugs andsolvates thereof, as blockers of Na⁺ channels. In view of this property,compounds of Formula I, and the pharmaceutically acceptable salts,prodrugs and solvates thereof, are useful for treating disordersresponsive to the blockade of sodium ion channels.

The compounds useful in this aspect of the invention are compoundsrepresented by Formula I:

and the pharmaceutically acceptable salts, prodrugs and solvatesthereof, wherein:

Z¹ is CR² or N, Z² is CR³ or N, Z³ is CR⁴ or N, Z⁴ is CR⁵ or N, and Z⁵is CR⁶ or N, provided that Z², Z³, Z⁴, and Z⁵ are not all N at the sametime;

G is G¹, G², or G³, wherein

G¹ is

G² is

G³ is

m is 0, 1, 2, or 3;

p is 0, 1, 2, or 3;

r is 0 or 1;

s is 1 or 2; provided that when r is 1, then s is 1;

R⁷ is selected from the group consisting of

a) —C(═O)NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently selectedfrom the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl;

b) —C(═O)OR¹², wherein R¹² is selected from the group consisting ofhydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;

c) —(CH₂)_(n)OR¹³, wherein n is 1, 2, 3, 4, or 5 and R¹³ is hydrogen;and

d) hydrogen;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl,alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy,haloalkylcarbonyl, and optionally substituted arylcarbonyl; or

—NR⁸R⁹ is —NO₂; or

R⁹ is hydrogen, R⁷ is —(CH₂)_(n)OR¹³, R⁸ and R¹³ together form a bridge—C(═O)— to form a heterocyclic ring, n is 1, 2, 3, 4, or 5, and m is 1,2 or 3;

R^(7a) is selected from the group consisting of

a) —(CH₂)_(q)OH, wherein q is 1, 2, 3, 4, or 5;

b) —C(═O)OR^(12a), wherein R^(12a) is selected from the group consistingof hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; and

c) hydrogen;

R^(8a) is hydrogen or a bond (—OR^(8a) is ═O), provided that when R^(7a)is hydrogen, then R^(8a) is hydrogen;

R^(7b) and R^(8b) are are each independently selected from the groupconsisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl,alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,hydroxy, haloalkylcarbonyl, and optionally substituted arylcarbonyl;

R^(9b) is hydrogen, alkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkyl,cyanoalkyl, or hydroxyalkyl;

one of R¹, R², R³, R⁴, R⁵, and R⁶ is A, wherein

A is

wherein

A¹ is aryl or heteroaryl, any of which is optionally substituted;

X is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NR²⁷—, —N(R²⁸)SO₂—, or —SO₂N(R²⁹)—,wherein

R²⁷, R²⁸, and R²⁹ are each independently hydrogen or alkyl; and

R¹⁴ and R¹⁵ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl;

R¹, when not A, is hydrogen, alkyl, hydroxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, aminocarbonylalkyl,(alkylaminocarbonyl)alkyl, or (dialkylaminocarbonyl)alkyl; and

R², R³, R⁴, R⁵, and R⁶, when not A, are each independently selected fromthe group consisting of hydrogen; optionally substituted alkyl (such as,for example, (2-oxooxazolidin-4-yl)alkyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂OH,—CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹, —CH(NR¹⁸R¹⁹)CH₂OH, andCH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are each independently hydrogenor C₁₋₆ alkyl), optionally substituted alkenyl, or optionallysubstituted alkynyl; halogen; hydroxy; cyano; amino; alkylamino;dialkylamino; alkoxy; aminocarbonyl; alkylaminocarbonyl;dialkylaminocarbonyl; alkylcarbonylamino; alkylcarbonyloxy; carboxy;aminosulfonyl; alkylsulfonylamino; and alkoxycarbonyl.

The carbon in G¹ to which NR⁸R⁹ is attached and the carbon in G² towhich OR^(8a) is attached can be chiral centers. The carbon in G³ towhich OH and R^(9b) are attached can be a chiral center. Accordingly,the configuration at those carbon atoms can be (R) or (S). R², R³, R⁴,R⁵, and R⁶, when not A, can also include a chiral center.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹ is A, and Z¹, Z², Z³, Z⁴, and Z⁵ are as defined forFormula I, wherein at least one of Z¹, Z², Z³, Z⁴, and Z⁵ is N, and thepharmaceutically acceptable salts, prodrugs, and solvates thereof. Inone aspect of this embodiment, Z¹ is N. In another aspect of thisembodiment, Z² is N. In another aspect of this embodiment, Z³ is N. Inanother aspect of this embodiment, Z⁴ is N. In another aspect of thisembodiment, Z⁵ is N.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Z¹ is CR², R² is A, and R¹, Z², Z³, Z⁴ and Z⁵ are asdefined for Formula I, wherein at least one of Z², Z³, Z⁴, and Z⁵ is N,and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof. In one aspect of this embodiment, Z² is N. In another aspect ofthis embodiment, Z³ is N. In another aspect of this embodiment, Z⁴ is N.In another aspect of this embodiment, Z⁵ is N.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Z² is CR³, R³ is A, and R¹, Z¹, Z³, Z⁴ and Z⁵ are asdefined for Formula I, wherein at least one of Z¹, Z³, Z⁴ and Z⁵ is N,and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof. In one aspect of this embodiment, Z¹ is N. In another aspect ofthis embodiment, Z³ is N. In another aspect of this embodiment, Z⁴ is N.In another aspect of this embodiment, Z⁵ is N.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Z³ is CR⁴, R⁴ is A, and R¹, Z¹, Z², Z⁴ and Z⁵ are asdefined for Formula I, wherein at least one of Z¹, Z², Z⁴ and Z⁵ is N,and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof. In one aspect of this embodiment, Z¹ is N. In another aspect ofthis embodiment, Z² is N. In another aspect of this embodiment, Z⁴ is N.In another aspect of this embodiment, Z⁵ is N.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Z⁴ is CR⁵, R⁵ is A, and R¹, Z¹, Z², Z³ and Z⁵ are asdefined for Formula I, wherein at least one of Z¹, Z², Z³ and Z⁵ is N,and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof. In one aspect of this embodiment, Z¹ is N. In another aspect ofthis embodiment, Z² is N. In another aspect of this embodiment, Z³ is N.In another aspect of this embodiment, Z⁵ is N.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Z⁵ is CR⁶, R⁶ is A, and R¹, Z¹, Z², Z³ and Z⁴ are asdefined for Formula I, wherein at least one of Z¹, Z², Z³ and Z⁴ is N,and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof. In one aspect of this embodiment, Z¹ is N. In another aspect ofthis embodiment, Z² is N. In another aspect of this embodiment, Z³ is N.In another aspect of this embodiment, Z⁴ is N.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Z⁵ is N, Z, Z², Z³, and Z⁴ are CR², CR³, CR⁴, and CR⁵,respectively, and G is G³, wherein r is 0, A¹ is optionally substitutedheteroaryl, and R¹ is A.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where at least two of Z¹, Z², Z³, Z⁴, and Z⁵ are N. Inanother embodiment, Z¹ and Z² are N, and Z³, Z⁴, and Z⁵ are CR⁴, CR⁵,and CR⁶, respectively. In another embodiment, Z¹ and Z³ are N, and Z²,Z⁴, and Z⁵ are CR³, CR⁵, and CR⁶, respectively. In another embodiment,Z¹ and Z⁴ are N, and Z², Z³, and Z⁵ are CR³, CR⁴, and CR⁶, respectively.In another embodiment, Z¹ and Z⁵ are N, and Z², Z³, and Z⁴ are CR³, CR⁴,and CR⁵, respectively.

In one embodiment, Compounds of the Invention are compounds of FormulaI, where Z¹, Z², Z³, Z⁴, and Z⁵ are CR², CR³, CR⁴, CR⁵, and CR⁶,respectively, which Compounds of the Invention have the Formula II:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein G and R¹-R⁶ are as defined for Formula I.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Z¹, Z², Z³, Z⁴, and Z⁵ are CR², CR³, CR⁴, CR⁵, and CR⁶respectively, R³, R⁵, and R⁶ are hydrogen, R⁴ is A, G is G¹, wherein R⁷and R⁸ are H and R⁹ is haloalkylcarbonyl or optionally substitutedarylcarbonyl, and R² is other than alkoxycarbonyl.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula II:

and pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein:

G is G¹ or G², wherein

G¹ is

and

G² is

m is 0, 1, 2, or 3;

p is 0, 1, 2, or 3;

R⁷ is selected from the group consisting of

a) —C(═O)NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently selectedfrom the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl;

b) —C(═O)OR¹², wherein R¹² is selected from the group consisting ofhydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;

c) —(CH₂)_(n)OR¹³, wherein n is 1-5 and R¹³ is hydrogen; and

d) hydrogen;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl,alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; or

—NR⁸R⁹ is —NO₂; or

R⁹ is hydrogen, R⁷ is —(CH₂)_(n)OR¹³, R⁸ and R¹³ together form a bridge—C(═O)— to form a heterocyclic ring, and m is 1, 2 or 3;

R^(7a) is selected from the group consisting of

a) —(CH₂)_(q)OH, wherein q is 1-5;

b) —C(═O)OR^(12a), wherein R^(12a) is selected from the group consistingof hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; and

c) hydrogen;

R^(8a) is hydrogen or a bond;

one of R¹, R², R³, R⁴, R⁵, and R⁶ is A, wherein

A is

wherein

A¹ is aryl or heteroaryl, any of which is optionally substituted;

X is —O—, —S—, —SO—, —SO₂—, —CH₂—, or —NH—; and

R¹⁴ and R¹⁵ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl;

R¹, when not A, is hydrogen; and

R², R³, R⁴, R⁵, and R⁶, when not A, are each independently selected fromthe group consisting of hydrogen; optionally substituted alkyl (such as,for example, (2-oxooxazolidin-4-yl)alkyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂OH,—CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹, —CH(NR¹⁸R¹⁹)CH₂OH, andCH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are each independently hydrogenor C₁₋₆ alkyl), optionally substituted alkenyl, or optionallysubstituted alkynyl; halogen; hydroxy; cyano; amino; alkylamino;dialkylamino; alkoxy; aminocarbonyl; alkylaminocarbonyl;dialkylaminocarbonyl; alkylcarbonylamino; alkylcarbonyloxy; carboxy;aminosulfonyl; and alkylsulfonylamino.

In compounds of Formulae I and II, when any of R⁸, R⁹, R¹⁰, R¹¹, R^(7b),R^(8b), or R¹ is hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, or dialkylaminoalkyl, the alkyl portion of R⁸, R⁹, R¹⁰,R¹¹, R^(7b), R^(8b), or R¹ that is attached to the nitrogen atomincludes at least two carbon atoms.

In one embodiment, Compounds of the Invention are compounds of FormulaII, where R¹ is A, which Compounds of the Invention have the FormulaIII:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein A, G, and R²-R⁶ are as defined above for Formulae I orII.

In another embodiment, Compounds of the Invention are compounds ofFormula II, where R² is A, which Compounds of the Invention have theFormula IV:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein A, G, R¹, and R³-R⁶ are as defined above for Formulae Ior II.

In another embodiment, Compounds of the Invention are compounds ofFormula II, where R³ is A, which Compounds of the Invention have theFormula V:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein A, G, R¹, R² and R⁴-R⁶ are as defined above forFormulae I or II.

In another embodiment, Compounds of the Invention are compounds ofFormula II, where R⁴ is A, which Compounds of the Invention have theFormula VI:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein A, G, R¹-R³, R⁵, and R⁶ are as defined above forFormulae I or II.

In another embodiment, Compounds of the Invention are compounds ofFormula II, where R⁵ is A, which Compounds of the Invention have theFormula VII:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein A, G, R¹-R⁴, and R⁶ are as defined above for Formulae Ior II.

In another embodiment, Compounds of the Invention are compounds ofFormula II, where R⁶ is A, which Compounds of the Invention have theFormula VIII:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein A, G, and R¹-R⁵ are as defined above for Formulae I orII.

In another embodiment, Compounds of the Invention are compounds ofFormula II, where R¹ is A, and R², R³, R⁵ and R⁶ are hydrogen, whichCompounds of the Invention have the Formula IX:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein A, G, and R⁴ are as defined above for Formulae I or II.

In another embodiment, Compounds of the Invention are compounds ofFormula II, where R¹ is hydrogen, and one of R²-R⁶ is A, and when not A,R²-R⁶ are hydrogen, which Compounds of the Invention have the Formula X:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein A and G are as defined above for Formulae I or II.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹ is A; Z¹ is N; Z², Z³, Z⁴ and Z⁵ are CR³, CR⁴, CR⁵and CR⁶, respectively; which Compounds of the Invention have the FormulaXI:

wherein R³, R⁴, R⁵, R⁶, and G are as defined above for Formula I, andthe pharmaceutically acceptable salts, prodrugs, and solvates thereof.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹ is A; Z² is N; Z¹, Z³, Z⁴ and Z⁵ are CR², CR⁴, CR⁵and CR⁶, respectively; which Compounds of the Invention have the FormulaXII:

wherein R², R⁴, R⁵, R⁶, and G are as defined above for Formula I, andthe pharmaceutically acceptable salts, prodrugs, and solvates thereof.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹ is A; Z⁴ is N; Z¹, Z², Z³, and Z⁵ are CR², CR³, CR⁴,and CR⁶, respectively; which Compounds of the Invention have the FormulaXIII:

wherein R², R³, R⁴, R⁶, and G are as defined above for Formula I, andthe pharmaceutically acceptable salts, prodrugs, and solvates thereof.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G¹:

wherein m, R⁷, R⁸, and R⁹ are as defined above for Formulae I and II.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G¹, and where R⁷ in G¹ is—C(═O)NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently selected fromthe group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl; preferably each of R¹⁰ and R¹¹ is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl,hydroxy(C₂₋₆)alkyl, C₁₋₄ alkoxy(C₂₋₆)alkyl, halo(C₁₋₆)alkyl,halo(C₁₋₄)alkoxy(C₂₋₆)alkyl, amino(C₂₋₆)alkyl, C₁₋₄alkylamino(C₂₋₆)alkyl, and di(C₁₋₄)alkylamino(C₂₋₆)alkyl; and morepreferably each of R¹⁰ and R¹¹ is independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, hydroxy(C₂₋₄)alkyl, C₁₋₂alkoxy(C₂₋₄)alkyl, halo(C₁₋₄)alkyl, halo(C₁₋₂)alkoxy(C₂₋₄)alkyl,amino(C₂₋₄)alkyl, C₁₋₂ alkylamino(C₂₋₄)alkyl, anddi(C₁₋₂)alkylamino(C₂₋₄)alkyl. In one embodiment, R¹⁰ and R¹¹ both arehydrogen. In another embodiment, R¹⁰ is hydrogen and R¹¹ is selectedfrom the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl; preferably R¹¹ is selected from the group consistingof C₁₋₆ alkyl, hydroxy(C₂₋₆)alkyl, C₁₋₄ alkoxy-(C₂₋₆)alkyl,halo(C₁₋₆)alkyl, halo(C₁₋₄)alkoxy(C₂₋₆)alkyl, amino(C₂₋₆)alkyl, C₁₋₄alkylamino(C₂₋₆)alkyl, and di(C₁₋₄)alkylamino(C₂₋₆)alkyl; and morepreferably R¹¹ is selected from the group consisting of C₁₋₄ alkyl,hydroxy(C₂₋₄)alkyl, C₁₋₂ alkoxy-(C₂₋₄)alkyl, halo(C₁₋₄)alkyl,halo(C₁₋₂)alkoxy(C₂₋₄)alkyl, amino(C₂₋₄)alkyl, C₁₋₂alkylamino(C₂₋₄)alkyl, and di(C₁₋₂)alkylamino(C₂₋₄)alkyl. In oneembodiment, R¹¹ is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 1,2-dihydroxyethyl,2,3-dihydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, trifluoromethyl,trifluoroethyl, 2-(trifluoromethoxy)ethyl, 2-aminoethyl,2-(methylamino)ethyl, or 2-(dimethylamino)ethyl. In one embodiment, R¹⁰is hydrogen and R¹¹ is hydroxyalkyl, such as hydroxy(C₂₋₄)alkyl, e.g.,2-hydroxyethyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G¹, and where R⁷ in G¹ is —C(═O)OR¹²,wherein R¹² is selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, and dialkylaminoalkyl; preferably R¹² is selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₄alkoxy(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, halo(C₁₋₄)alkoxy(C₁₋₆)alkyl,amino(C₁₋₆)alkyl, C₁₋₄ alkylamino(C₁₋₆)alkyl, anddi(C₁₋₄)alkylamino(C₁₋₆)alkyl; and more preferably R¹² is selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, hydroxy(C₁ 4)alkyl, C₁₋₂alkoxy(C₁ 4)alkyl, halo(C₁₋₄)alkyl, halo(C₁₋₂)alkoxy(C₁₋₄)alkyl,amino(C₁₋₄)alkyl, C₁₋₂ alkylamino(C₁₋₄)alkyl, anddi(C₁₋₂)alkylamino(C₁₋₄)alkyl. In one embodiment, R¹² is methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, 1,2-dihydroxyethyl,2,3-dihydroxypropyl, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl,ethoxymethyl, trifluoromethyl, 2-trifluoroethyl, trifluoromethoxymethyl,trifluoroethoxymethyl, aminomethyl, 2-aminoethyl, methylaminomethyl,2-(methylamino)ethyl, dimethylaminomethyl, or 2-(dimethylamino)ethyl.Typically, R¹² is hydrogen or alkyl, and more preferably hydrogen orC₁₋₄ alkyl, such as methyl, ethyl, propyl, iso-propyl, butyl, ortert-butyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G¹, and where R⁷ in G¹ is—(CH₂)_(n)OR¹³, wherein n is 1, 2, 3, 4, or 5 and R¹³ is hydrogen.Preferably, n is 1, 2, or 3, and more preferably 1 or 2.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G¹, and where R⁷ in G¹ is hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G¹, and where R⁸ and R⁹ are eachindependently selected from the group consisting of hydrogen, alkyl,alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, andoptionally substituted arylcarbonyl. In another embodiment, Compounds ofthe Invention are compounds of any of Formulae I-XIII, wherein G is G¹,and where R⁸ and R⁹ are each independently selected from the groupconsisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl,alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl.Useful compounds of the present invention include compounds of any ofFormulae I-XIII, where R⁸ and R⁹ are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl,hydroxy(C₂₋₆)alkyl, C₁₋₄ alkoxy(C₂₋₆)alkyl, halo(C₁₋₆)alkyl,halo(C₁₋₄)alkoxy(C₂₋₆)alkyl, amino(C₂₋₆)alkyl, C₁₋₄alkylamino(C₂₋₆)alkyl, and di(C₁₋₄)alkylamino(C₂₋₆)alkyl; preferablyeach of R⁸ and R⁹ is independently selected from the group consisting ofhydrogen, C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl, C₁₋₄alkylcarbonyl, C₁₋₄ alkoxycarbonyl, hydroxy(C₂₋₄)alkyl, C₁₋₂alkoxy(C₂₋₄)alkyl, halo(C₁₋₄)alkyl, halo(C₁₋₂)alkoxy(C₂₋₄)alkyl,amino(C₂₋₄)alkyl, C₁₋₂ alkylamino(C₂₋₄)alkyl, and di(C₁2)alkylamino(C₂₋₄)alkyl; and typically each of R⁸ and R⁹ isindependently selected from the group consisting of hydrogen, C₁₋₄methyl, C₁₋₄ alkylsulfonyl, and C₁₋₄ alkoxycarbonyl. Useful compoundsinclude those where R⁸ and R⁹ are each independently selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl. In oneembodiment, R⁸ and R⁹ and both hydrogen. In another embodiment, R⁸ ishydrogen, and R⁹ is C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl,C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, hydroxy(C₂₋₆)alkyl, C₁₋₄alkoxy(C₂₋₆)alkyl, halo(C₁₋₆)alkyl, halo(C₁₋₄)alkoxy(C₂₋₆)alkyl,amino(C₂₋₆)alkyl, C₁₋₄ alkylamino(C₂₋₆)alkyl, ordi(C₁₋₄)alkylamino(C₂₋₆)alkyl; preferably R⁹ is C₁₋₄ alkyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylcarbonyl, C₁₋₄alkoxycarbonyl, hydroxy(C₂₋₄)alkyl, C₁₋₂ alkoxy(C₂₋₄)alkyl,halo(C₁₋₄)alkyl, halo(C₁₋₂)alkoxy(C₂₋₄)alkyl, amino(C₂₋₄)alkyl, C₁₋₂alkylamino(C₂₋₄)alkyl, or di(C₁₋₂)alkylamino(C₂₋₄)alkyl; more preferablyR⁹ is C₁₋₄ methyl, C₁₋₄ alkylsulfonyl, and C₁₋₄ alkoxycarbonyl; andtypically R⁹ is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, and tert-butoxycarbonyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G¹, and where —NR⁸R⁹ is —NO₂.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G¹, R⁷ is —(CH₂)_(n)OR¹³, n is 1, 2, 3,4, or 5, m is 1, 2, or 3, R⁹ is hydrogen and R⁸ and R¹³ together form abridge —C(═O)— to form a heterocyclic ring. Preferably, n is 1, 2, or 3,and more preferably n is 1. In this embodiment, useful compounds includethose where m is 1 or 2, and preferably 1. In one embodiment, G¹ is(2-oxooxazolidin-4-yl)C₁₋₃ alkyl, and typically(2-oxooxazolidin-4-)methyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where m is 1 or 2. Typically, m is 1.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G¹, and where G¹ is selected from thegroup consisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G¹, and where G¹ is selected from thegroup consisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G¹, and where G¹ is selected from thegroup consisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G¹ and R⁷ is hydrogen. In thisembodiment, useful compounds include compounds of any of Formulae I-XIIIwhere G¹ is

In this embodiment, when G¹ is

A is A″, R³, R⁴, R⁵, and R⁶ is hydrogen, R¹ is A, R¹⁴ and R¹⁵ are bothhydrogen then at least one of R¹⁶ or R¹⁷ is selected from alkyl,alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro,amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino,thiol, acyloxy, azido, alkoxy, carboxy, and aminocarbonyl.

-   R¹ is A″, and Z¹, Z², Z³, Z⁴, and Z⁵ are CR², CR³, CR⁴, CR⁵, and    CR⁶, respectively, then preferably at least one of R², R³, R⁴, R⁵,    and R⁶ is other than hydrogen, and preferably selected from the    group consisting of carboxy, aminocarbonyl, amino, aminosulfonyl,    methylsulfonylamino, methyl, ethyl, propyl, isopropyl, butyl,    (2-oxooxazolidin-4-yl)methyl, (2-oxooxazolidin-4-yl)ethyl,    —CH(OH)C(═O)NH₂, —CH(OH)CH₂OH, —CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹,    —CH(NR¹⁸R¹⁹)CH₂OH, and —CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are    each independently hydrogen or C₁₋₆ alkyl. Typically, in this    embodiment, R², R³, R⁵, and R⁶ are each hydrogen, and R⁴ is selected    from the group consisting of carboxy, aminocarbonyl, amino,    aminosulfonyl, methylsulfonylamino, methyl, ethyl, propyl,    isopropyl, butyl, (2-oxooxazolidin-4-yl)methyl,    (2-oxooxazolidin-4-yl)ethyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂OH,    —CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹, —CH(NR¹⁸R¹⁹)CH₂OH, and    —CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are each independently    hydrogen or C₁₋₆ alkyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G²:

wherein p, R^(7a), and R^(8a) are as defined above for Formula I.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G², and where R^(7a) in G² is—(CH₂)_(q)OH, wherein q is 1, 2, 3, 4, or 5. Typically, q is 1, 2, or 3.More typically, q is 1 or 2, and specifically q is 1.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G², and where R^(7a) in G² is—C(═O)OR^(12a), wherein R^(12a) is selected from the group consisting ofhydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; preferably R^(12a)is selected from the group consisting of hydrogen, C₁₋₆ alkyl,hydroxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, halo(C₁₋₆)alkyl,halo(C₁₋₄)alkoxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, C₁₋₄alkylamino(C₁₋₆)alkyl, and di(C₁₋₄)alkylamino(C₁₋₆)alkyl; and morepreferably R^(12a) is selected from the group consisting of hydrogen,C₁₋₄ alkyl, hydroxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, halo(C₁₋₄)alkyl,halo(C₁₋₂)alkoxy(C₁₋₄)alkyl, amino(C₁₋₄)alkyl, C₁₋₂alkylamino-(C₁₋₄)alkyl, and di(C₁₋₂)alkylamino(C₁₋₄)alkyl. In oneembodiment, R^(12a) is methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,4-hydroxybutyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl, methoxymethyl,2-methoxyethyl, 3-methoxypropyl, ethoxymethyl, trifluoromethyl,2-trifluoroethyl, trifluoromethoxymethyl, trifluoroethoxymethyl,aminomethyl, 2-aminoethyl, methylaminomethyl, 2-(methylamino)ethyl,dimethylaminomethyl, or 2-(dimethylamino)ethyl. Typically, R^(12a) ishydrogen or alkyl, and more preferably hydrogen or C₁₋₄ alkyl, such asmethyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G², and where R^(7a) in G² is hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G², and where R^(8a) in G² is hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G², and where Rsa in G² is a bond(—OR^(8a) is ═O).

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G², and where G² is selected from thegroup consisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G², and where G² is selected from thegroup consisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G², and where G² is selected from thegroup consisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G², and where G² is —C(═O)—C(═O)—OH.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³:

wherein R^(7b), R^(8b), R^(9b), r, and s are as defined above forFormula I.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³ and r in G³ is 0.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³, and r in G³ is 1 and R^(9b) is asdefined above for Formula I. In one embodiment, Compounds of theInvention are compounds of any of Formulae I-XIII, where G is G³, r is 1and R^(9b) is hydrogen. In another embodiment, Compounds of theInvention are compounds of any of Formulae I-XIII, where R^(9b) isalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkyl, cyanoalkyl, orhydroxyalkyl. In this embodiment, useful compounds of the presentinvention include those where R^(9b) is C₁₋₆ alkyl, halo(C₁₋₆)alkyl,halo(C₁₋₄)alkoxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, cyano(C₁₋₆)alkyl,or hydroxy(C₁₋₆)alkyl; preferably C₁₋₄ alkyl, halo(C₁₋₄)alkyl,halo(C₁₋₂)alkoxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, cyano(C₁₋₄)alkyl,or hydroxy(C₁₋₄)alkyl; and typically R^(9b) is methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, fluoromethyl, difluoromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,trichloromethyl, trifluoromethoxymethyl, trifluoroethoxymethyl,methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, ethoxymethyl,cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, 1,2-dihydroxyethyl, or2,3-dihydroxypropyl. Typically, R^(9b) is hydrogen or haloalkyl, andmore preferably hydrogen or halo(C₁₋₄)alkyl, such as fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, and trichloromethyl; and more preferably hydrogenor trifluoromethyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³ and s in G³ is 1.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³ and s in G³ is 2.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³ and r in G³ is 0 and s is 1.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³ and r in G³ is 0 and s is 2.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³ and r in G³ is 1 and s is 1.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³ and R^(7b) and R^(8b) are bothhydrogen.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³, R^(7b) in G³ is hydrogen and R^(8b)is alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, oroptionally substituted arylcarbonyl; preferably R^(8b) is C₁₋₆ alkyl,C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, hydroxy(C₂₋₆)alkyl, C₁₋₆ alkoxy(C₂₋₆)alkyl,halo(C₁₋₆)alkyl, halo(C₁₋₄)alkoxy(C₂₋₆)alkyl, amino(C₂₋₆)alkyl, C₁₋₄alkylamino(C₂₋₆)alkyl, di(C₁₋₄)alkylamino(C₂₋₆)alkyl, hydroxy,halo(C₁₋₄)alkylcarbonyl, or optionally substituted benzoyl; morepreferably R^(8b) is C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, hydroxy(C₂₋₆)alkyl, C₁₋₄alkoxy(C₂₋₆)alkyl, halo(C₁₋₄)alkyl, halo(C₁₋₂)alkoxy(C₂₋₄)alkyl,amino(C₂₋₄)alkyl, C₁₋₂ alkylamino(C₂₋₄)alkyl,di(C₁₋₂)alkylamino(C₂₋₄)alkyl, hydroxy, halo(C₁₋₄)alkylcarbonyl, orbenzoyl optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, halogen,halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, andC₁₋₄ alkoxy.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where G is G³, and R^(7b) and R^(8b) in G³ are eachindependently selected from the group consisting of alkyl,alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, andoptionally substituted arylcarbonyl; preferably R^(7b) and R^(8b) areeach independently selected from the group consisting of C₁₋₆ alkyl,C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, hydroxy(C₂₋₆)alkyl, C₁₋₆ alkoxy(C₂₋₆)alkyl,halo(C₁₋₆)alkyl, halo(C₁₋₄)alkoxy(C₂₋₆)alkyl, amino(C₂₋₆)alkyl, C₁₋₄alkylamino(C₂₋₆)alkyl, di(C₁₋₄)alkylamino(C₂₋₆)alkyl, hydroxy,halo(C₁₋₄)alkylcarbonyl, and optionally substituted benzoyl; andtypically R^(7b) and R^(8b) are each independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, hydroxy(C₂₋₄)alkyl, C₁₋₄alkoxy(C₂₋₄)alkyl, halo(C₁₋₄)alkyl, halo(C₁₋₂)alkoxy(C₂₋₄)alkyl,amino(C₂₋₄)alkyl, C₁₋₂ alkylamino(C₂₋₄)alkyl,di(C₁₋₂)alkylamino(C₂₋₄)alkyl, hydroxy, halo(C₁₋₂)alkylcarbonyl, andbenzoyl optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, halogen,halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, andC₁₋₄ alkoxy.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G³, and where r is 0, s is 1 or 2,R^(7b) is hydrogen and R^(8b) is hydrogen, hydroxy, or hydroxyalkyl;preferably R^(8b) is hydrogen, hydroxy, or hydroxy(C₂₋₄)alkyl; morepreferably R^(8b) is hydrogen, hydroxy, 2-hydroxyethyl, 3-hydroxypropyl,4-hydroxybutyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl,3,4-dihydroxybutyl, or 2,4-dihydroxybutyl. In this embodiment, R^(8b) istypically hydrogen, hydroxy, 2-hydroxyethyl, or 2,3-dihydroxypropyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G³, and where r is 1, s is 1, R^(9b) ishydrogen, R^(7b) is hydrogen and R^(8b) is hydrogen, hydroxy, orhydroxyalkyl; preferably R^(8b) is hydrogen, hydroxy, orhydroxy(C₂₋₄)alkyl; more preferably R^(8b) is hydrogen, hydroxy,2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 1,2-dihydroxyethyl,2,3-dihydroxypropyl, 3,4-dihydroxybutyl, or 2,4-dihydroxybutyl. In thisembodiment, R^(8b) is typically hydrogen, hydroxy, 2-hydroxyethyl, or2,3-dihydroxypropyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G³, and where r is 1, s is 1, R^(9b) ishaloalkyl or haloalkoxyalkyl, R^(7b) is hydrogen and R^(8b) is hydrogen,hydroxy, or hydroxyalkyl; preferably R^(8b) is hydrogen, hydroxy, orhydroxy(C₂₋₄)alkyl; more preferably R^(8b) is hydrogen, hydroxy,2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 1,2-dihydroxyethyl,2,3-dihydroxypropyl, 3,4-dihydroxybutyl, or 2,4-dihydroxybutyl. In thisembodiment, R^(8b) is typically hydrogen. In this embodiment, R^(9b) ispreferably halo(C₁₋₆)alkyl or halo(C₁₋₄)alkoxy(C₁₋₆)alkyl; morepreferably R^(9b) is halo(C₁₋₄)alkyl or halo(C₁₋₂)alkoxy(C₁₋₄)alkyl; andmore preferably R^(9b) is fluoromethyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, trichloromethyl,trifluoromethoxymethyl, or trifluoroethoxymethyl; and typically R^(9b)is trifluoromethyl or trichloromethyl, and advantageouslytrifluoromethyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII where G is G³, and where G³ is selected from thegroup consisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII where G is G³, and where G³ is selected from thegroup consisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII where G is G³, and where G³ is selected from thegroup consisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII where G is G³, and where G³ is selected from thegroup consisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where A¹ is an optionally substituted heteroaryl. Inone embodiment, A¹ is a 5-6 membered heteroaryl ring having at least onenitrogen atom. Typical heteroaryl groups for A¹ include 6-memberedheteroaryl groups having at least one nitrogen atom, such as pyridyl(pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), pyrimidinyl(pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, or pyrimidin-6-yl),pyridazinyl (pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, orpyridazin-6-yl), and pyrazinyl (pyrazin-2-yl or pyrazin-3-yl).Typically, the heteroaryl group is optionally substituted with 1 or 2substituents. Typical optional substituents include alkyl, alkenyl,alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano,amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy,azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl; preferablyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro,amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido,C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl, C₁₋₄alkoxy, carboxy, and aminocarbonyl. Typically, the 1 or 2 substituentsare each independently selected from the group consisting of C₁₋₄ alkyl,halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino,cyano, and C₁₋₄ alkoxy, and more typically are each independentlyselected from the group consisting of fluoro, bromo, trifluoromethyl,and cyano. In one embodiment, Compounds of the Invention are compoundsof any of Formulae I-XIII, where A¹ is unsubstituted or substitutedpyridyl, such as pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. In oneembodiment, A¹ is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl optionallysubstituted with 1 or 2 substituents each independently selected fromthe group consisting of alkyl (for example, C₁₋₄ alkyl, such as methylor ethyl), haloalkyl (for example, halo(C₁₋₄)alkyl, such astrifluoromethyl) and halogen. In another embodiment, A¹ is pyridin-2-ylsubstituted at the 5-position. In this embodiment, the substituent istypically halogen, cyano, or haloalkyl, such as trihaloalkyl, andspecifically trifluoromethyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where A¹ is an optionally substituted aryl. In oneembodiment, A¹ is unsubstituted phenyl. In another embodiment, A¹ isphenyl substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl; preferably eachsubstituent is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each substituent is independentlyselected from the group consisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro,amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido,C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl, C₁₋₄alkoxy, carboxy, and aminocarbonyl. Typically, the 1, 2, or 3substituents are each independently selected from the group consistingof C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy,nitro, amino, cyano, and C₁₋₄ alkoxy, and more typically are eachindependently selected from the group consisting of fluoro, bromo,trifluoromethyl, and cyano. In one embodiment, A¹ is phenyl substitutedat the 4-position. In this embodiment, the substituent is typicallyhalogen, cyano, or haloalkyl, such as trihaloalkyl, and specificallytrifluoromethyl. In another embodiment, A¹ is phenyl substituted withtwo substituents, which can be the same or different, at the 3- and4-positions. In this embodiment, the two substituents are independentlyselected from the group consisting of halogen, cyano and haloalkyl (suchas trihaloalkyl, and specifically trifluoromethyl). In anotherembodiment, A¹ is phenyl substituted with cyano and trifluoromethyl atthe 3- and 4-positions of the phenyl group, respectively.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where X is —O—, —S—, or —SO₂—. Typical compounds ofthe present invention include those where X is —O— or —S—. In anotherembodiment, Compounds of the Invention are those where X is —O—.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where X is —NR²⁷—, wherein R²⁷ is hydrogen or alkyl,preferably hydrogen or C₁₋₄ alkyl, and typically hydrogen or methyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where X is —N(R²⁸)SO₂— or —SO₂N(R²⁹)—, where R²⁸ andR²⁹ are as defined above for Formula I. In one embodiment, X is—N(R²⁸)SO₂—. In another embodiment, X is —SO₂N(R²⁹)—. Preferably, R²⁸and R²⁹ are each independently hydrogen or C₁₋₄ alkyl, and typicallyhydrogen or methyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where A is A¹ having the structure:

whereinX is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NR²⁷—, —N(R²⁸)SO₂— or —SO₂N(R²⁹)—,where R²⁷, R²⁸, and R²⁹ are each independently hydrogen or alkyl; andR¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R¹⁴, R¹⁵, R¹⁶,and R¹⁷ is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R¹⁴, R¹⁵, R¹⁶, and R¹⁷ isindependently selected from the group consisting of C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy, and aminocarbonyl. Typically,R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are each independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, and C₁₋₄ alkoxy. Moretypically, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are each independently selected fromthe group consisting of hydrogen, fluoro, bromo, trifluoromethyl, andcyano. In this aspect of the invention, compounds useful in the presentinvention are those where X is —O— or —S—. In another embodiment,Compounds of the Invention are compounds of any of Formulae I-XIII,wherein A is A¹, X is —O—, —S—, —SO—, —SO₂—, —CH₂—, or —NH—, and R¹⁴,R¹⁵, R¹⁶ and R¹⁷ are as defined above. In another embodiment, X in A¹ is—NR²⁷—, and typically —NH—. In another embodiment, X in A¹ is—N(R²⁸)SO₂— or —SO₂N(R²⁹)—, and preferably —N(R²⁸)SO₂—, where R²⁸ ishydrogen or C₁₋₄ alkyl, and preferably hydrogen or methyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where A is A″ having the structure:

whereinR¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R¹⁴, R¹⁵, R¹⁶,and R¹⁷ is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R¹⁴, R¹⁵, R¹⁶, and R¹⁷ isindependently selected from the group consisting of C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy, and aminocarbonyl. Typically,R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined above for A¹.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹ is A″ and R²-R⁶ are hydrogen, which Compounds of theInvention have the Formula XIV:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹⁰ and R¹¹ are as defined above for Formula I, andR¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl. Preferable definitions for R¹⁰, R¹,R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are those described above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹ is H, one of R²-R⁶ is A″, and R², R³, R⁴, R⁵, or R⁶,when not A″, is hydrogen, which Compounds of the Invention have theFormula XV:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹⁰ and R¹¹ are as defined above for Formula I, andR¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined above for Formula XIV. Preferabledefinitions for R¹⁰, R¹¹, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are those describedabove.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹ is A″, and R², R³, R⁴, R⁵, and R⁶ are each hydrogen,which Compounds of the Invention have the Formula XVI:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined above for FormulaXIV. Preferable definitions for R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are thosedescribed above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹ is H, one of R²-R⁶ is A″, and R², R³, R⁴, R⁵, or R⁶,when not A″, is hydrogen, which Compounds of the Invention have theFormula XVII:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined above for FormulaXIV. Preferable definitions for R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are thosedescribed above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹ is A″ and R²-R⁶ are hydrogen, which Compounds of theInvention have the Formula XVIII:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where R¹ is A″ and R²-R⁶ are hydrogen, which Compounds of theInvention have the Formula XIX:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl.

In another embodiment, Compounds of the Invention include those of anyof Formulae XIV-XIX, where R¹⁴ and R¹⁵ are both hydrogen and R¹⁶ and R¹⁷are each independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl (includingmonohydroxyalkyl and dihydroxyalkyl), hydroxy, nitro, amino, cyano,amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy,azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl. Typically, R¹⁶and R¹⁷ are each independently selected from the group consisting ofhydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, C₁₋₄ alkoxy, and carboxy, and moretypically R¹⁶ and R¹⁷ are each independently selected from the groupconsisting of hydrogen, fluoro, bromo, trifluoromethyl, and cyano. Inone embodiment, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ each are hydrogen. In oneembodiment, R¹⁴, R¹⁵ and R¹⁶ are hydrogen and R¹⁷ is alkyl, alkenyl,alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano,amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy,azido, mercaptoalkyl, alkoxy, carboxy, or aminocarbonyl; preferably R¹⁷is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,or aminocarbonyl; and more preferably R¹⁷ is C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy,nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl,ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl,C₁₋₄ alkoxy, carboxy, or aminocarbonyl. Typically, R¹⁷ is selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, and C₁₋₄ alkoxy. Moretypically, R¹⁷ is selected from the group consisting of hydrogen,fluoro, bromo, trifluoromethyl, and cyano. In one embodiment, R¹⁷ is atthe 4-position of the phenyl ring (i.e., at the para-position). In thisembodiment, the substituent is typically halogen, cyano, or haloalkyl,such as trihaloalkyl, and specifically trifluoromethyl. In anotherembodiment, R¹⁴ and R¹⁵ are both hydrogen and R¹⁶ and R¹⁷, which can bethe same or different, are at the 3- and 4-positions of the phenyl ring(i.e., at the meta- and para-positions). In this embodiment, R¹⁶ and R¹⁷are typically independently selected from the group consisting ofhalogen, cyano and haloalkyl (such as trihaloalkyl, and specificallytrifluoromethyl). In another embodiment, R¹⁶ is cyano and R¹⁷ istrifluoromethyl at 3- and 4-positions of the phenyl group, respectively.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where A is A′″ having the structure:

whereinX is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NR²⁷—, —N(R²⁸)SO₂— or —SO₂N(R²⁹)—,where R²⁷, R²⁸, and R²⁹ are each independently hydrogen or alkyl; andR¹⁴, R¹⁵, R³⁰, and R³¹ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R¹⁴, R¹⁵, R³⁰,and R³¹ is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R¹⁴, R¹⁵, R³⁰, and R³¹ isindependently selected from the group consisting of C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy, and aminocarbonyl. Typically,R¹⁴, R¹⁵, R³⁰ and R³¹ are each independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, and C₁₋₄ alkoxy. Moretypically, R¹⁴, R¹⁵, R³⁰ and R³¹ are each independently selected fromthe group consisting of hydrogen, fluoro, bromo, trifluoromethyl, andcyano. In one embodiment, R¹⁴ and R¹⁵ are both hydrogen, and R³⁰ and R³¹are each independently selected from the group consisting of hydrogen,fluoro, bromo, trifluoromethyl, and cyano. In this aspect of theinvention, compounds useful in the present invention are those where Xis —O— or —S—. In another embodiment, X in A′″ is —NR²⁷—, and typically—NH—. In another embodiment, X in A′″ is —N(R²⁸)SO₂— or —SO₂N(R²⁹)—, andpreferably —N(R²⁸)SO₂—, where R²⁸ is hydrogen or C₁₋₄ alkyl, andpreferably hydrogen or methyl.

In another embodiment, Compounds of the Invention include those of anyof Formulae I-XIII, where A is A′″, and R¹⁴ and R¹⁵ in A′″ are bothhydrogen and R³⁰ and R³¹ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl (including monohydroxyalkyl and dihydroxyalkyl), hydroxy,nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl. Typically, R³⁰ and R³¹ are each independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, halogen,halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, C₁₋₄alkoxy, and carboxy, and more typically R³⁰ and R³¹ are eachindependently selected from the group consisting of hydrogen, fluoro,bromo, trifluoromethyl, and cyano. In one embodiment, R¹⁴, R¹⁵, R³⁰ andR³¹ each are hydrogen. In one embodiment, R¹⁴, R¹⁵ and R³⁰ are hydrogenand R³¹ is alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, oraminocarbonyl; preferably R³¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,halogen, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino,cyano, amide, carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆acylamino, thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy,carboxy, or aminocarbonyl; and more preferably R³¹ is C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy, or aminocarbonyl. Typically,R³¹ is selected from the group consisting of hydrogen, C₁₋₄ alkyl,halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino,cyano, and C₁₋₄ alkoxy. More typically, R³¹ is selected from the groupconsisting of hydrogen, fluoro, bromo, trifluoromethyl, and cyano. Inone embodiment, R³¹ is at the 5-position of the pyridin-2-yl ring. Inthis embodiment, the substituent is typically halogen, cyano, orhaloalkyl, such as trihaloalkyl, and specifically trifluoromethyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where A is A″″ having the structure:

whereinR¹⁴, R¹⁵, R³⁰, and R³¹ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R¹⁴, R¹⁵, R³⁰,and R³¹ is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R¹⁴, R¹⁵, R³⁰, and R³¹ isindependently selected from the group consisting of C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy, and aminocarbonyl. Typically,R¹⁴, R¹⁵, R³⁰ and R³¹ are as defined above for A′″.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where R¹, when not A, is hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, where R¹, when not A, is alkyl, hydroxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonylalkyl,(alkylaminocarbonyl)alkyl, or (dialkylaminocarbonyl)alkyl; preferablyC₁₋₆ alkyl, hydroxy(C₂₋₆)alkyl, amino(C₂₋₆)alkyl, C₁₋₄alkylamino(C₂₋₆)alkyl, di(C₁₋₄)alkylamino(C₂₋₆)alkyl,aminocarbonyl(C₁₋₆)alkyl, (C₁₋₄ alkylaminocarbonyl)(C₁₋₆)alkyl, or(di(C₁ 4)alkylaminocarbonyl)(C₁₋₆)alkyl; and more preferably C₁₋₄ alkyl,hydroxy(C₂₋₄)alkyl, amino(C₂₋₄)alkyl, C₁₋₂ alkylamino(C₂₋₄)alkyl,di(C₁₋₂)alkylamino(C₂₋₄)alkyl, aminocarbonyl(C₁₋₄)alkyl, (C₁₋₂alkylaminocarbonyl)(C₁₋₄)alkyl, or(di(C₁₋₂)alkylaminocarbonyl)(C₁₋₄)alkyl. In this embodiment, R¹ istypically hydroxy(C₂₋₄)alkyl, amino(C₂₋₄)alkyl, C₁₋₂alkylamino(C₂₋₄)alkyl, di(C₁₋₂)alkylamino(C₂₋₄)alkyl, oraminocarbonyl(C₁₋₄)alkyl, such as 2-hydroxyethyl, 3-hydroxypropyl,1,2-dihydroxyethyl, 2,3-dihydroxypropyl, 2-aminoethyl, 3-aminopropyl,2-(methylamino)ethyl, 3-(methylamino)propyl, 2-(ethylamino)ethyl,3-(ethylamino)propyl, 2-(dimethylamino)ethyl, 3-(dimethylamino)propyl,2-(methylethylamino)ethyl, 3-(methylethylamino)propyl,2-(diethylamino)ethyl, 3-(diethylamino)propyl, aminocarbonylmethyl,2-(aminocarbonyl)ethyl, and 3-(aminocarbonyl)propyl. In one embodiment,R¹ when not A, is 2-hydroxyethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl,2,3-dihydroxypropyl, 2-(dimethylamino)ethyl, 3-(dimethylamino)propyl,2-(diethylamino)ethyl, 3-(diethylamino)propyl, aminocarbonylmethyl,2-(aminocarbonyl)ethyl, or 3-(aminocarbonyl)propyl.

In another embodiment, Compounds of the Invention include those of anyone of Formulae I-IX and XI-XIII, where R², R³, R⁴, R⁵, and R⁶, when notA, are each independently selected from the group consisting ofhydrogen; optionally substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; halogen; hydroxy; cyano; amino; C₁₋₆ alkylamino;di(C₁₋₆)alkylamino; C₁₋₆ alkoxy; aminocarbonyl; C₁₋₆ alkylaminocarbonyl;di(C₁₋₆)alkylaminocarbonyl; C₁₋₆ alkylcarbonylamino; C₁₋₆alkylcarbonyloxy; carboxy; aminosulfonyl; C₁₋₆ alkylsulfonylamino; andC₁₋₆ alkoxycarbonyl; more preferably each is independently selected fromthe group consisting of hydrogen; optionally substituted C₁₋₄ alkyl,C₂₋₄ alkenyl, or C₂₋₄ alkynyl; halogen; hydroxy; cyano; amino; C₁₋₄alkylamino; di(C₁₋₄)alkylamino; C₁₋₄ alkoxy; aminocarbonyl; C₁₋₄alkylaminocarbonyl; di(C₁₋₄)alkylaminocarbonyl; C₁₋₄ alkylcarbonylamino;C₁₋₄ alkylcarbonyloxy; carboxy; aminosulfonyl; C₁₋₄ alkylsulfonylamino;and C₁₋₄ alkoxycarbonyl; and more preferably each is independentlyselected from the group consisitng of hydrogen; unsubstituted C₁₋₄alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl; C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of hydroxy, amino, carboxamido (e.g.,—C(═O)NH₂), and heterocyclo (e.g., 2-oxooxazolidin-4-yl); halogen;hydroxy; cyano; amino; C₁₋₂ alkylamino; di(C₁₋₂)alkylamino; C₁₋₂ alkoxy;aminocarbonyl; C₁₋₂ alkylaminocarbonyl; di(C₁₋₂)alkylaminocarbonyl; C₁₋₂alkylcarbonylamino; C₁₋₂ alkylcarbonyloxy; carboxy; aminosulfonyl; C₁₋₂alkylsulfonylamino; and C₁₋₂ alkoxycarbonyl. In another embodiment,Compounds of the Invention include those of any one of Formulae I-IX andXI-XIII, where R², R³, R⁴, R⁵, and R⁶, when not A, are eachindependently selected from the group consisting of hydrogen; optionallysubstituted C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; halogen; hydroxy;cyano; amino; C₁₋₆ alkylamino; di(C₁₋₆)alkylamino; C₁₋₆ alkoxy;aminocarbonyl; C₁₋₆ alkylaminocarbonyl; di(C₁₋₆)alkylaminocarbonyl; C₁₋₆alkylcarbonylamino; C₁₋₆ alkylcarbonyloxy; carboxy; aminosulfonyl; andC₁₋₆ alkylsulfonylamino.

In another embodiment, Compounds of the Invention include those of anyone of Formulae I-IX and XI-XIII, where R², R³, R⁴, R⁵, and R⁶, when notA, are each independently selected from the group consisting ofhydrogen, methyl, ethyl, propyl, isopropyl, butyl,(2-oxooxazolidin-4-yl)methyl, (2-oxooxazolidin-4-yl)ethyl,—CH(OH)C(═O)NH₂, —CH(OH)CH₂OH, —CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹,—CH(NR¹⁸R¹⁹)CH₂OH, —CH₂CH(NR¹⁸R¹⁹)CH₂OH (where R¹⁸ and R¹⁹ are eachindependently hydrogen or C₁₋₆ alkyl), carboxy, aminocarbonyl, amino,aminosulfonyl, methylsulfonylamino, halogen (especially F), cyano, andmethoxycarbonyl. In one embodiment, R¹ is A, R², R³, R⁵, and R⁶ are eachhydrogen, and R⁴ is at the 5-position and is as defined above;preferably R⁴ is selected from the group consisting of carboxy,aminocarbonyl, amino, aminosulfonyl, methylsulfonylamino, methyl, ethyl,propyl, isopropyl, butyl, halogen (especially F), cyano,methoxycarbonyl, (2-oxooxazolidin-4-yl)methyl,(2-oxooxazolidin-4-yl)ethyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂OH,—CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹, —CH(NR¹⁸R¹⁹)CH₂OH, and—CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are each independently hydrogenor C₁₋₆ alkyl; and more preferably R⁴ is selected from the groupconsisting of carboxy, aminocarbonyl, amino, aminosulfonyl,methylsulfonylamino, propyl, isopropyl, butyl, halogen (especially F),cyano, methoxycarbonyl, (2-oxooxazolidin-4-yl)methyl,(2-oxooxazolidin-4-yl)ethyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂OH,—CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹, —CH(NR¹⁸R¹⁹)CH₂OH, and—CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are each independently hydrogenor C₁₋₆ alkyl.

In another embodiment, Compounds of the Invention include those of anyone of Formulae I-IX and XI-XIII, where R², R³, R⁴, R⁵, and R⁶, when notA, are each independently selected from the group consisting ofhydrogen, methyl, ethyl, propyl, isopropyl; butyl,(2-oxooxazolidin-4-yl)methyl, (2-oxooxazolidin-4-yl)ethyl,—CH(OH)C(═O)NH₂, —CH(OH)CH₂OH, —CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹,—CH(NR¹⁸R¹⁹)CH₂OH, —CH₂CH(NR¹⁸R¹⁹)CH₂OH (where R¹⁸ and R¹⁹ are eachindependently hydrogen or C₁₋₆ alkyl), carboxy, aminocarbonyl, amino,aminosulfonyl, and methylsulfonylamino. In one embodiment, R¹ is A, R²,R³, R⁵, and R⁶ are each hydrogen, and R⁴ is at the 5-position and is asdefined above; preferably R⁴ is selected from the group consisting ofcarboxy, aminocarbonyl, amino, aminosulfonyl, methylsulfonylamino,methyl, ethyl, propyl, isopropyl, butyl, (2-oxooxazolidin-4-yl)methyl,(2-oxooxazolidin-4-yl)ethyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂OH,—CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹, —CH(NR¹⁸R¹⁹)CH₂OH, and—CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are each independently hydrogenor C₁₋₆ alkyl; and more preferably R⁴ is selected from the groupconsisting of carboxy, aminocarbonyl, amino, aminosulfonyl,methylsulfonylamino, propyl, isopropyl, butyl,(2-oxooxazolidin-4-yl)methyl, (2-oxooxazolidin-4-yl)ethyl,—CH(OH)C(═O)NH₂, —CH(OH)CH₂OH, —CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹,—CH(NR¹⁸R¹⁹)CH₂OH, and —CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are eachindependently hydrogen or C₁₋₆ alkyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-IX, XI, and XII, where R¹ is A, R², R³, R⁴, and R⁶ areeach hydrogen, and R⁵ is at the 6-position and is as defined above;preferably R⁵ is selected from the group consisting of carboxy,aminocarbonyl, amino, aminosulfonyl, methylsulfonylamino, methyl, ethyl,propyl, isopropyl, butyl, halogen (especially F), cyano,methoxycarbonyl, (2-oxooxazolidin-4-yl)methyl,(2-oxooxazolidin-4-yl)ethyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂OH,—CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹, —CH(NR¹⁸R¹⁹)CH₂OH, and—CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are each independently hydrogenor C₁₋₆ alkyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-IX and XI-XIII, where R¹ is A, R², R³, R⁴, and R⁵ are eachhydrogen, and R⁶ is at the 7-position and is as defined above;preferably R⁶ is selected from the group consisting of carboxy,aminocarbonyl, amino, aminosulfonyl, methylsulfonylamino, methyl, ethyl,propyl, isopropyl, butyl, halogen (especially F), cyano,methoxycarbonyl, (2-oxooxazolidin-4-yl)methyl,(2-oxooxazolidin-4-yl)ethyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂OH,—CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹, —CH(NR¹⁸R¹⁹)CH₂OH, and—CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are each independently hydrogenor C₁₋₆ alkyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-IX, XI, and XIII, where R¹ is A, R², R⁴, R⁵, and R⁶ areeach hydrogen, and R³ is at the 4-position and is as defined above;preferably R³ is selected from the group consisting of carboxy,aminocarbonyl, amino, aminosulfonyl, methylsulfonylamino, methyl, ethyl,propyl, isopropyl, butyl, halogen (especially F), cyano,methoxycarbonyl, (2-oxooxazolidin-4-yl)methyl,(2-oxooxazolidin-4-yl)ethyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂OH,—CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹, —CH(NR¹⁸R¹⁹)CH₂OH, and—CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are each independently hydrogenor C₁₋₆ alkyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XIII, wherein G is G³, wherein r and s in G³ are both 1,and R^(7b), R^(8b), and R^(9b) are ach hydrogen. In this embodiment, R¹is typically A, where A is preferably A″ or A″″.

In another embodiment, Compounds of the Invention are compounds ofFormula II, wherein G is G¹ which is

R¹ is A″, and at least one of R², R³, R⁴, R⁵, and R⁶ is selected fromthe group consisting of carboxy, aminocarbonyl, amino, aminosulfonyl,methylsulfonylamino, methyl, ethyl, propyl, isopropyl, butyl,(2-oxooxazolidin-4-yl)methyl, (2-oxooxazolidin-4-yl)ethyl,—CH(OH)C(═O)NH₂, —CH(OH)CH₂OH, —CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹,—CH(NR¹⁸R¹⁹)CH₂OH, and —CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are eachindependently hydrogen or C₁₋₆ alkyl. Typically, in this embodiment, R²,R³, R⁵, and R⁶ are each hydrogen, and R⁴ is selected from the groupconsisting of carboxy, aminocarbonyl, amino, aminosulfonyl,methylsulfonylamino, propyl, isopropyl, butyl,(2-oxooxazolidin-4-yl)methyl, (2-oxooxazolidin-4-yl)ethyl,—CH(OH)C(═O)NH₂, —CH(OH)CH₂OH, —CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹,—CH(NR¹⁸R¹⁹)CH₂OH, and —CH₂CH(NR¹⁸R¹⁹)CH₂OH, where R¹⁸ and R¹⁹ are eachindependently hydrogen or C₁₋₆ alkyl.

Optional substituents attached to aryl, phenyl, and heteroaryl ringseach take the place of a hydrogen atom that would otherwise be presentin any position on the aryl, phenyl or heteroaryl rings, respectively.

In another embodiment, Compounds of the Invention include:

-   2-amino-3-[7-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,-   2-amino-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,-   2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,-   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,-   2-amino-N-(2-hydroxyethyl)-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide,-   2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,-   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,-   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl    ester,-   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid,-   2-methanesulfonylamino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide,-   2-tert-butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic    acid,-   2-amino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,-   2-tert-butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic    acid ethyl ester,-   2-nitro-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl    ester,-   5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,-   5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,-   5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,-   4-{[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one,-   2-amino-3-[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol,-   2-(1-(4-phenoxyphenyl)-1H-indol-3-yl)ethanamine,-   5-{4-[3-(1,2-dihydroxyethyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)-benzonitrile,-   5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,-   5-{4-[3-(2-ethoxyoxalyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)-benzonitrile,-   5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}benzonitrile,-   and the pharmaceutically acceptable salts, prodrugs and solvates    thereof.-   In another embodiment, Compounds of the Invention include:-   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-oxoacetamide,-   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,-   methyl    3-(2-amino-1-hydroxy-2-oxoethyl)-1-(4-(3-cyano-4-(trifluoromethyl)-phenoxy)phenyl)-1H-indole-3-carboxylate,-   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-oxoacetamide,-   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-hydroxyacetamide,-   3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H-indole-1,3-diyl)bis(propane-1,2-diol),-   4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,-   4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,-   3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,-   3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,-   4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-N-methylbenzenesulfonamide,-   4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-benzenesulfonamide,-   2-(1-(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2-oxoacetic    acid,-   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carbonitrile,-   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-5-carbonitrile,-   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-7-carbonitrile,-   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carbonitrile,-   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxamide,-   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carboxamide,-   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxylic    acid,-   5-(4-(4-(1,2-dihydroxyethyl)-3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,-   (N)-(2-hydroxyethyl)-1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,-   1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,-   N-hydroxy-1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,-   5-fluoro-1-(4-(4-trifluoromethyl)phenoxy)phenyl)-1H-indazole-3-carboxamide,-   1-(4-(3-cyano-(4-trifluoromethyl)phenoxy)phenyl)-1H-indazole-3-carboxamide,    1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indazole-3-carboxamide,-   1-(4-(4-cyanophenoxy)phenyl)-N-(2,3-dihydroxypropyl)-1H-indazole-3-carboxamide,-   (1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methanol,-   1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol,-   3-(1-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol,-   4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenoxy)benzonitrile,-   2-(1-(2-diethylamino)ethyl-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)-2-oxoacetamide,-   2-(1-(2-(diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,-   3-(1-(2-diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,-   2-(3-(2,3-dihydroxypropyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide,-   2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanamide,-   2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,-   2-hydroxy-2-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)acetamide,-   2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol,-   3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol,-   and the pharmaceutically acceptable salts, prodrugs and solvates    thereof.-   In another embodiment, Compounds of the Invention include:-   (S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,-   (R)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,-   (S)-5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,-   (S)-4-{[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one,-   (S)-2-amino-3-[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol,-   (S)-5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,-   (S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-benzonitrile,

and the pharmaceutically acceptable salts, prodrugs and solvatesthereof.

In another embodiment, Compounds of the Invention include:

-   (S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-oxoacetamide,-   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N—((S)-2,3-dihydroxypropyl)-2-hydroxyacetamide,-   (2S,2′S)-3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H-indole-1,3-diyl)bis(propane-1,2-diol),-   (S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,-   (R)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,-   (S)-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,-   (S)-3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,-   (S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-N-methylbenzenesulfonamide,-   (S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-benzenesulfonamide,-   (R)-2-(1-(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2-oxoacetic    acid,-   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carbonitrile,-   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-5-carbonitrile,-   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-7-carbonitrile,-   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carbonitrile,-   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxamide,-   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carboxamide,-   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxylic    acid,-   5-(4-(4-(1,2-dihydroxyethyl)-3-((R)-2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,-   5-(4-(4-(1,2-dihydroxyethyl)-3-((S)-2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,-   (R)-1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol,-   (S)-3-(1-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol,-   (S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenoxy)benzonitrile,-   (S)-3-(1-(2-diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,-   (S)-2-(3-(2,3-dihydroxypropyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide,-   (S)-2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol,-   (S)-3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol,-   (S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,-   (R)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,

and the pharmaceutically acceptable salts, prodrugs and solvatesthereof.

The present invention is also directed to the compounds of Formula XX:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are each independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl; preferably each ofR¹⁴, R¹⁵, R¹⁶, and R¹⁷ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen,halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano,amide, carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆acylamino, thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy,carboxy, and aminocarbonyl; and more preferably each of R¹⁴, R¹⁵, R¹⁶,and R¹⁷ is independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino,thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy,and aminocarbonyl. Typically, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined abovefor A¹. In one embodiment, a compound of Formula XX isN,N-diethyl-2-(5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)ethanamine,or a pharmaceutically acceptable salt, prodrug or solvate thereof.

The present invention also relates to the use of compounds of Formula XXas intermediates for preparing compounds of Formula I.

The present invention also relates to compounds of Formula XX, and thepharmaceutically acceptable salts, prodrugs and solvates thereof, foruse in treating pain (e.g., acute pain, chronic pain, which includes butis not limited to, neuropathic pain, postoperative pain and inflammatorypain, or surgical pain) in a mammal.

Further, the present invention relates to compounds of Formula XX, andthe pharmaceutically acceptable salts, prodrugs and solvates thereof,for use in treating stroke, neuronal damage resulting from head trauma,epilepsy, seizures, general epilepsy with febrile seizures, severemyoclonic epilepsy in infancy, neuronal loss following global and focalischemia, migraine, familial primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, distonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia in a mammal.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups are selected from straight-chain and branched-chainC₁₋₁₀ alkyl groups. Typical C₁₋₁₀ alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, pentyl,3-pentyl, hexyl, heptyl, octyl, nonyl and decyl, among others. In oneembodiment, useful alkyl groups are selected from straight chain C₁₋₆alkyl groups and branched chain C₃₋₆ alkyl groups. Typical C₁₋₆ alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, iso-butyl, pentyl, 3-pentyl, hexyl, among others. In oneembodiment, useful alkyl groups are selected from straight chain C₁₋₄alkyl groups and branched chain C₃₋₄ alkyl groups. Typical C₁₋₄ alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, iso-butyl.

Useful cycloalkyl groups are selected from saturated and partiallyunsaturated (containing one or two double bonds) cyclic hydrocarbongroups containing one to three rings having from three to twelve carbonatoms (i.e., C₃-C₁₂ cycloalkyl) or the number of carbons designated. Inone embodiment, the cycloalkyl has one or two rings. In anotherembodiment, the cycloalkyl is a C₃-C₈ cycloalkyl. Exemplary cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl and the like. Inone embodiment, the cycloalkyl group contains one double bond.Preferably, the cycloalkyl groups containing one double bond have fromfour to twelve carbon atoms (i.e., C₄-C₁₂ cycloalkenyl). Exemplarycycloalkyl groups containing one double bond include cyclobuenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,cyclodecenyl, among others. In another embodiment, the cycloalkyl groupcontains two double bonds. Preferably, the cycloalkyl groups containingtwo double bonds have from five to twelve carbon atoms (i.e., C₅-C₁₂cycloalkadienyl). Exemplary cycloalkyl groups having two double bondsinclude cyclopentadienyl, cyclohexadienyl, cycloheptadienyl,cyclooctadienyl, cyclononadienyl, cyclodecadienyl, among others.

Useful alkenyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkenyl groups, preferably C₂₋₄ alkenyl. TypicalC₂₋₆ alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,sec-butenyl, pentenyl, and hexenyl. Typical C₂₋₄ alkenyl groups includeethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.

Useful alkynyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkynyl groups, preferably C₂₋₄ alkynyl. TypicalC₂₋₆ alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl,pentynyl, and hexynyl groups. Typical C₂₋₄ alkynyl groups includeethynyl, propynyl, butynyl, and 2-butynyl groups.

Useful haloalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by one or more fluorine, chlorine, bromine or iodineatoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andtrichloromethyl groups).

Useful hydroxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by one or more hydroxy groups, such asmonohydroxyalkyl and dihydroxyalkyl groups (e.g., hydroxymethyl,hydroxyethyl, hydroxypropyl and hydroxybutyl groups, and especiallyhydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3-hydroxybutyl,4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl).

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy,iso-propoxy, butoxy, tert-butoxy, iso-butoxy, sec-butoxy, pentyloxy,hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy).

Useful alkoxyalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted with any of the above-mentioned alkoxy groups (e.g.,methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl,2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, propoxymethyl,iso-propoxymethyl, 2-propoxyethyl, 3-propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl).

Useful haloalkoxy groups include oxygen substituted by one of the C₁₋₁₀haloalkyl groups mentioned above (e.g., fluoromethoxy, difluoromethoxy,trifluoromethoxy, and 2,2,2-trifluoroethoxy).

Useful haloalkoxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted with any of the above-mentioned haloalkoxygroups (e.g., fluoromethoxymethyl, difluoromethoxymethyl,trifluoromethoxymethyl, 2-(trifluoromethoxy)ethyl, and2,2,2-trifluoroethoxymethyl).

Useful (cycloalkyl)alkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted with any of the above-mentioned cycloalkylgroups (e.g., cyclopropylmethyl, 2-(cyclopropyl)ethyl,cyclopropylpropyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, and the like).

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups, more preferablyphenyl, naphthyl, and biphenyl groups.

Useful aryloxy groups include oxygen substituted by one of the arylgroups mentioned above (e.g., phenoxy).

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by any of the above-mentioned aryl groups (e.g.,benzyl, phenethyl, and the like).

Useful aralkyloxy groups include oxygen substituted by one of theabove-mentioned arylalkyl groups (e.g., benzyloxy).

The term “heteroaryl” or “heteroaromatic” as employed herein refers togroups having 5 to 14 ring atoms, with 6, 10 or 14 π electrons shared ina cyclic array, and containing carbon atoms and 1, 2, or 3 oxygen,nitrogen or sulfur heteroatoms, or 4 nitrogen atoms. Examples ofheteroaryl groups include thienyl, benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl,isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl,quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, (3-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, andphenoxazinyl. Typical heteroaryl groups include thienyl (e.g.,thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl(e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g.,2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl),thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl),isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, andisothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, andoxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, andisoxazol-5-yl).

The terms “heterocyclic” and “heterocyclo” are used herein to meansaturated or wholly or partially unsaturated 3-7 membered monocyclic, or7-10 membered bicyclic ring system, which consist of carbon atoms andfrom one to four heteroatoms independently selected from the groupconsisting of O, N, and S, wherein the nitrogen and sulfur heteroatomscan be optionally oxidized, the nitrogen can be optionally quaternized,and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring, and wherein theheterocyclic ring can be substituted on a carbon atom or on a nitrogenatom if the resulting compound is stable. In one embodiment, the 3- to7-membered monocyclic heterocyclic ring is either saturated, orunsaturated non-aromatic ring. A 3-membered heterocyclo can contain upto 1 heteroatom, a 4-membered heterocyclo can contain up to 2heteroatoms, a 5-membered heterocyclo can contain up to 4 heteroatoms, a6-membered heterocyclo can contain up to 4 heteroatoms, and a 7-memberedheterocyclo can contain up to 5 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 3- to 7-memberedheterocyclo can be attached via a nitrogen or carbon atom. A 7- to10-membered bicyclic heterocyclo contains from 1 to 4 heteroatomsindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 7- to 10-memberedbicyclic heterocyclo can be attached via a nitrogen or carbon atomExamples of the include, but are not limited to, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, imidazolinyl, pyrazolidinyl,tetrahydrofuranyl, oxazolidinyl, 2-oxooxazolidinyl, tetrahydrothienyl,imidazolidinyl, hexahydropyrimidinyl, benzodiazepines, and the like.

Useful heterocycloalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heterocyclicgroups (e.g., (pyrrolidin-2-yl)methyl, (pyrrolidin-1-yl)methyl,(piperidin-1-yl)methyl, (morpholin-1-yl)methyl,(2-oxooxazolidin-4-yl)methyl, 2-(2-oxooxazolidin-4-yl)ethyl, and thelike).

As used herein, the term “amino” or “amino group” refers to —NH₂.

Useful aminoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted with an amino group.

Useful diaminoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted with two amino groups.

Useful alkylamino and dialkylamino groups are —NHR²⁰ and —NR²⁰R²¹,respectively, wherein R²⁰ and R²¹ are each independently selected from aC₁₋₁₀ alkyl group.

Useful hydroxyalkylamino groups are —NHR²⁰, wherein R²⁰ is any of theabove-mentioned hydroxyalkyl groups.

Useful alkylaminoalkyl and dialkylaminoalkyl groups are any of theabove-mentioned C₁₋₁₀ alkyl groups substituted by any of theabove-mentioned alkylamino and dialkylamino groups, respectively.

As used herein, the term “aminocarbonyl” refers to —C(═O)NH₂.

As used herein, the term “aminocarbonylalkyl” refers to any of theabove-captioned C₁₋₁₀ alkyl groups substituted with an aminocarbonylgroup (e.g., aminocarbonylmethyl, 2-(aminocarbonyl)ethyl, and3-(aminocarbonyl)propyl).

As used herein, the term “aminosulfonyl” refers to —SO₂NH₂.

Useful alkylcarbonyl groups include a carbonyl group, i.e., —C(═O)—,substituted by any of the above-mentioned C₁₋₁₀ alkyl groups.

Useful alkoxycarbonyl groups include a carbonyl group substituted by anyof the above-mentioned alkoxy groups (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, iso-butoxycarbonyl, sec-butoxycarbonyl, andpentyloxycarbonyl).

Useful haloalkylcarbonyl groups include a carbonyl group substituted byany of the above-mentioned haloalkyl groups (e.g., fluoromethylcarbonyl,difluoromethylcarbonyl, trifluoromethylcarbonyl,pentafluoroethylcarbonyl, 1,1-difluoroethylcarbonyl,2,2-difluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl,3,3,3-trifluoropropylcarbonyl, 4,4,4-trifluorobutylcarbonyl, andtrichloromethylcarbonyl).

Useful arylcarbonyl groups include a carbonyl group substituted by anyof the above-mentioned aryl groups (e.g., benzoyl).

Useful alkylcarbonyloxy or acyloxy groups include oxygen substituted byone of the above-mentioned alkylcarbonyl groups.

Useful alkylcarbonylamino or acylamino groups include any of theabove-mentioned alkylcarbonyl groups attached to an amino nitrogen, suchas methylcarbonylamino.

As used herein, the term “carboxamido” refers to a radical of formula—C(═O)NR²²R²³, wherein R²² and R²³ are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary carboxamido groups include —CONH₂, —CON(H)CH₃, —CON(CH₃)₂, and—CON(H)Ph and the like

Useful alkylaminocarbonyl and dialkylaminocarbonyl groups are any of theabove-mentioned carboxamido groups, where R²² is H and R²³ is C₁₋₁₀alkyl or where R²² and R²³ are each independently selected from a C₁₋₁₀alkyl group, respectively.

Useful (alkylaminocarbonyl)alkyl and (dialkylaminocarbonyl)alkyl groupsare any of the above-mentioned C₁₋₁₀ alkyl groups substituted with analkylaminocarbonyl or a dialkylaminocarbonyl group, respectively.

As used herein, the term “sulfonamido” refers to a radical of formula—SO₂NR²⁴R²⁵, wherein R²⁴ and R²⁵ are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary sulfonamido groups include —SO₂NH₂, —SO₂N(H)CH₃, —SO₂N(H)Phand the like.

As used herein, the term “alkylsulfonyl” refers to —SO₂R²⁶, wherein R²⁶is any of the above-mentioned C₁₋₁₀ alkyl groups.

As used herein, the term “alkylsulfinyl” refers to —S(═O)R²⁶, whereinR²⁶ is any of the above-mentioned C₁₋₁₀ alkyl groups.

As used herein, the term “alkylsulfonylamino” refers to —N(H)SO₂R²⁶wherein R²⁶ is any of the above-mentioned C₁₋₁₀ alkyl groups.

Useful mercaptoalkyl groups include any of the above-mentioned C₁-10alkyl groups substituted by a —SH group.

As used herein, the term “carboxy” refers to —COOH.

Useful carboxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by —COOH.

As used herein, the term “cyano” refers to —CN.

Useful cyanoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by —CN.

As used herein, the term “ureido” refers to —NH—C(═O)—NH₂.

As used herein, the term “azido” refers to —N₃.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment.

As used herein, the term “optionally substituted” refers to a group thatmay be unsubstituted or substituted.

Optional substituents on optionally substituted groups, when nototherwise indicated, include one or more groups, typically 1, 2, or 3groups, independently selected from the group consisting of halo,halo(C₁₋₆)alkyl, aryl, heterocycle, cycloalkyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl,aryl(C₂₋₆)alkynyl, cycloalkyl(C₁₋₆)alkyl, heterocyclo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl,alkoxy(C₁₋₆)alkyl, nitro, amino, ureido, cyano, alkylcarbonylamino,hydroxy, thiol, alkylcarbonyloxy, aryloxy, ar(C₁₋₆)alkyloxy,carboxamido, sulfonamido, azido, C₁₋₆ alkoxy, halo(C₁₋₆)alkoxy, carboxy,aminocarbonyl, and mercapto(C₁₋₆)alkyl groups mentioned above. Preferredoptional substituents include halo, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy,halo(C₁₋₆)alkoxy, and amino.

The invention disclosed herein is also meant to encompass prodrugs ofany of the disclosed compounds. As used herein, prodrugs are consideredto be any covalently bonded carriers that release the active parent drugin vivo. In general, such prodrugs will be a functional derivative of acompound of Formula I-XX which is readily convertible in vivo, e.g., bybeing metabolized, into the required compound of Formula I-XX.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described in, for example, Design of Prodrugs,H. Bundgaard ed., Elsevier (1985); “Drug and Enzyme Targeting, Part A,”K. Widder et al. eds., Vol. 112 in Methods in Enzymology, Academic Press(1985); Bundgaard, “Design and Application of Prodrugs,” Chapter 5 (pp.113-191) in A Textbook of Drug Design and Development, P.Krogsgaard-Larsen and H. Bundgaard eds., Harwood Academic Publishers(1991); Bundgaard et al., Adv. Drug Delivery Revs. 8:1-38 (1992);Bundgaard et al., J. Pharmaceut. Sci. 77:285 (1988); and Kakeya et al.,Chem. Pharm. Bull. 32:692 (1984). Non-limiting examples of prodrugsinclude esters or amides of compounds of any of Formulae I-XX havinghydroxyalkyl or aminoalkyl as a substituent, and these may be preparedby reacting such parent compounds with anhydrides such as succinicanhydride.

The invention disclosed herein is also intended to encompass any of thedisclosed compounds being isotopically-labelled (i.e., radiolabeled) byhaving one or more atoms replaced by an atom having a different atomicmass or mass number. Examples of isotopes that can be incorporated intothe disclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, 35S, F, and ³⁶Cl, respectively, andpreferably ³H, ¹¹C, and ¹⁴C. Isotopically-labeled compounds of thepresent invention can be prepared by methods known in the art.

The present invention is also directed specifically to ³H, ¹¹C, or ¹⁴Cradiolabeled compounds of any of Formulae I-XX, as well as theirpharmaceutically acceptable salts, prodrugs and solvates, and the use ofany such compounds as radioligands for their binding site on the calciumchannel. For example, one use of the labeled compounds of the presentinvention is the characterization of specific receptor binding. Anotheruse of a labeled compound of the present invention is an alternative toanimal testing for the evaluation of structure-activity relationships.For example, the receptor assay may be performed at a fixedconcentration of a labeled compound of the invention and at increasingconcentrations of a test compound in a competition assay. For example, atritiated compound of any of Formulae I-XX can be prepared byintroducing tritium into the particular compound, for example, bycatalytic dehalogenation with tritium. This method may include reactinga suitably halogen-substituted precursor of the compound with tritiumgas in the presence of a suitable catalyst, for example, Pd/C, in thepresence or absence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6(1987). ¹⁴C-labeled compounds can be prepared by employing startingmaterials having a ¹⁴C carbon.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present invention is meant toencompass the uses of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers maybe separated according to methods known to those of ordinary skill inthe art in view of the present disclosure. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that theyinclude both E and Z geometric isomers. All tautomers are intended to beencompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treating” or “treatment” is meant to encompass administeringto a subject a compound of the present invention for the purposes ofamelioration or cure, including preemptive and palliative treatment.

The term “R^(8a) is a bond” for —OR^(8a) refers to the formation of an═O group with the carbon atom to which the —OR^(8a) group is attached.

When numeric ranges are provided for parameters, e.g. the parameterbeing 1-5 then it is meant that all of the integers inbetween are alsoencompassed, such as n is 1-5 or q is 1-5 means that n and q areselected from 1, 2, 3, 4, or 5.

The invention disclosed herein also encompasses the use of salts of thedisclosed compounds, including all non-toxic pharmaceutically acceptablesalts thereof of the disclosed compounds. Examples of pharmaceuticallyacceptable addition salts include inorganic and organic acid additionsalts and basic salts. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,cesium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide,phosphate, sulphate and the like; organic acid salts such as citrate,lactate, tartrate, maleate, fumarate, mandelate, acetate,dichloroacetate, trifluoroacetate, oxalate, formate and the like;sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularcompound of the present invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present invention with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

The invention disclosed herein is also meant to encompass solvates ofany of the disclosed compounds. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present invention with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present invention is 2:1, 1:1 or 1:2,respectively. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances, the solvate can be isolated, such as when one or more solventmolecules are incorporated into the crystal lattice of a crystallinesolid. Thus, “solvate” encompasses both solution-phase and isolatablesolvates. Compounds of any of Formulae I-XX may be present as solvatedforms with a pharmaceutically acceptable solvent, such as water,methanol, ethanol, and the like, and it is intended that the inventionincludes both solvated and unsolvated forms of compounds of any ofFormulae I-XX. One type of solvate is a hydrate. A “hydrate” relates toa particular subgroup of solvates where the solvent molecule is water.Solvates typically can function as pharmacological equivalents.Preparation of solvates is known in the art. See, for example, M. Cairaet al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparation of solvates, hemisolvates, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun.: 603-604(2001). A typical, non-limiting, process of preparing a solvate wouldinvolve dissolving a compound of any of Formulae I-XX in a desiredsolvent (organic, water, or a mixture thereof) at temperatures aboveabout 20° C. to about 25° C., then cooling the solution at a ratesufficient to form crystals, and isolating the crystals by knownmethods, e.g., filtration. Analytical techniques such as infraredspectroscopy can be used to confirm the presence of the solvent in acrystal of the solvate.

Since compounds of Formulae I-XX are blockers of sodium (Na⁺) channels,a number of diseases and conditions mediated by sodium ion influx can betreated by employing these compounds. The present invention is thusdirected generally to a method for treating a disorder responsive to theblockade of sodium channels in an animal suffering from, or at risk ofsuffering from, said disorder, said method comprising administering tothe animal an effective amount of a compound represented by any ofdefined Formulae I-XX, or a pharmaceutically acceptable salt, prodrug orsolvate thereof.

The present invention is further directed to a method of modulating, inparticular blocking sodium channels in an animal in need thereof, saidmethod comprising administering to the animal at least one compoundrepresented by any of defined Formulae I-XX, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof.

More specifically, the present invention provides a method of treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, pain (e.g.,acute pain, chronic pain, which includes but is not limited toneuropathic pain, postoperative pain and inflammatory pain, or surgicalpain), migraine, familial primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, distonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia. In one embodiment, theinvention provides a method of treating pain. In another embodiment, thetype of pain treated is chronic pain. In another embodiment, the type ofpain treated is neuropathic pain. In another embodiment, the type ofpain treated is postoperative pain. In another embodiment, the type ofpain treated is inflammatory pain. In another embodiment, the type ofpain treated is surgical pain. In another embodiment, the type of paintreated is acute pain. In another embodiment, the treatment of pain(e.g., chronic pain, such as neuropathic pain or inflammatory pain,acute pain or surgical pain) is preemptive. In another embodiment, thetreatment of pain is palliative. In each instance, such method oftreatment requires administering to an animal in need of such treatmentan amount of a compound of the present invention that is therapeuticallyeffective in achieving said treatment. In one embodiment, the amount ofsuch compound is the amount that is effective as to block sodiumchannels in vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 2000; 18: 387-391).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogenous disease state with an unclearetiology. In chronic neuropathic pain, the pain can be mediated bymultiple mechanisms. This type of pain generally arises from injury tothe peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiences. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-XX, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament for treating a disorder responsive to the blockade of sodiumchannels (e.g., any of the disorders listed above) in an animalsuffering from said disorder.

Furthermore, the present invention is directed to a method ofmodulating, in particular blocking sodium channels in an animal in needthereof, said method comprising administering to the animal at least onecompound represented by any defined Formulae I-XX, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-XX, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament, in particular a medicament for modulating, in particularblocking sodium channels, in an animal in need thereof.

Synthesis of Compounds

The compounds of the present invention can be prepared using methodsknown to those skilled in the art in view of this disclosure. Forexample, compounds of Formula I can be prepared as shown in Schemes 1-5.Additional methods of synthesis are described and illustrated in theworking examples set forth below.

In Scheme 1, A is as defined for Formula I. Ref. 1: (a) Quick et al.,Tetrahedron Letters 35(46): 8549-52 (1994); and (b) Quick et al.,Heterocycles 39(2): 571-579 (1994). Ref. 2: Kozikowski et al., Journalof the American Chemical Society 111(16): 6228-6234 (1989).

In Scheme 2, A, R¹⁰ and R¹¹ are as defined for Formula I and R¹ is analkyl.

In Scheme 3, A is as defined for Formula I, R′″ is hydrogen, and R¹¹ is,for example, hydrogen, optionally substituted alkyl (such as, forexample, —CH(OH)CH₂OH, —CH₂CH(OH)CH₂OH, —CH(OH)CH₂NR¹⁸R¹⁹, or—CH(NR¹⁸R¹⁹)CH₂OH), alkenyl, or alkynyl, halogen, hydroxy, cyano, amino,alkylamino, dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, or alkylcarbonylamino. Ref. 3: Doyle et al.,Journal of Organic Chemistry 50(10): 1663-1666 (1985).

In Scheme 4, A, R⁸ and R⁹ are as defined for Formula I.

In Scheme 5, A is as defined for Formula I.

In Scheme 6, R¹¹ is as defined in Scheme 3, and A, R^(7b) and R^(8b) areas defined for Formula I.

In Scheme 7, A, R¹, R^(7b), and R^(8b) are as defined for Formula I.Testing of Compounds

Compounds of the present invention were assessed by sodium mobilizationand/or electrophysiological assays for sodium channel blocker activity.One aspect of the present invention is based on the use of the compoundsherein described as sodium channel blockers. Based upon this property,compounds of the present invention are considered useful in treating acondition or disorder responsive to the blockade of sodium ion channels,e.g., stroke, neuronal damage resulting from head trauma, epilepsy,seizures, general epilepsy with febrile seizures, severe myoclonicepilepsy in infancy, neuronal loss following global and focal ischemia,a neurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), migraine, familialprimary erythromelalgia, paroxysmal extreme pain disorder, cerebellaratrophy, ataxia, distonia, tremor, mental retardation, autism, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia. The compounds of the presentinvention are also expected to be effective in treating pain, such asacute pain, chronic pain, which includes but is not limited toneuropathic pain, postoperative pain and inflammatory pain, or surgicalpain.

More specifically, the present invention is directed to compounds ofFormulae I-XX that are blockers of sodium channels. According to thepresent invention, those compounds having useful sodium channel blockingproperties exhibit an IC₅₀ for Na_(v)1.1, Na_(v)1.2, Na_(v)1.3,Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7, Na_(v)1.8 and/or Na_(v)1.9of about 100 μM or less, e.g., about 50 μM or less, about 10 μM or less,about 5 μM or less, or about 1 μM or less, in the sodium mobilizationand/or electrophysiological assays described herein. In certainembodiments, compounds of the present invention exhibit an IC₅₀ forNa_(v)1.7 of 100 μM or less, e.g., about 50 μM or less, about 10 μM orless, about 5 μM or less, or about 1 μM or less, about 0. μM or less, orabout 0.1 μM or less. Compounds of the present invention can be testedfor their Na⁺ channel blocking activity using methods well known in theart and by the following fluorescence imaging and electrophysiologicalin vitro assays and/or in vivo assays.

In vitro Assay Protocols

FLIPR® Assays:

Recombinant Na_(v)1.7 Cell Line:

In vitro assays were performed in a recombinant cell line expressingcDNA encoding the alpha subunit (Na_(v)1.7, SCN9a, PN1, NE) of humanNa_(v)1.7 (Accession No. NM_002977). The cell line was provided byinvestigators at Yale University (Cummins et al, J Neurosci. 18(23):9607-9619 (1998)). For dominant selection of the Na_(v)1.7-expressingclones, the expression plasmid co-expressed the neomycin resistancegene. The cell line was constructed in the human embryonic kidney cellline, HEK293, under the influence of the CMV major late promoter, andstable clones were selected using limiting dilution cloning andantibiotic selection using the neomycin analogue, G418. Recombinant betaand gamma subunits were not introduced into this cell line. Additionalcell lines expressing recombinant Na_(v)1.7 cloned from other speciescan also be used, alone or in combination with various beta subunits,gamma subunits or chaperones.

Non-Recombinant Cell Lines Expressing Native Na_(v)1.7:

Alternatively, in vitro assays can be performed in a cell lineexpressing native, non-recombinant Na_(v)1.7, such as the ND7 mouseneuroblastoma X rat dorsal root ganglion (DRG) hybrid cell line ND7/23,available from the European Cell Culture Collection (Cat. No. 92090903,Salisbury, Wiltshire, United Kingdom). The assays can also be performedin other cell lines expressing native, non-recombinant Na_(v)1.7, fromvarious species, or in cultures of fresh or preserved sensory neurons,such as dorsal root ganglion (DRG) cells, isolated from various species.Primary screens or counter-screens of other voltage-gated sodiumchannels to can also be performed, and the cell lines can be constructedusing methods known in the art, purchased from collaborators orcommercial establishments, and they can express either recombinant ornative channels. The primary counter-screen is for one of the centralneuronal sodium channels, Na_(v)1.2 (rBIIa), expressed in HEK293 hostcells (Ilyin et al., Br. J. Pharmacol. 144:801-812 (2005)).Pharmacological profiling for these counter-screens is carried out underconditions similar to the primary or alternative Na_(v)1.7 assaysdescribed below.

Cell Maintenance:

Unless otherwise noted, cell culture reagents were purchased fromMediatech of Herndon, Va. The recombinant Na_(v)1.7/HEK293 cells wereroutinely cultured in growth medium consisting of Dulbecco's minimumessential medium containing 10% fetal bovine serum (FBS, Hyclone, ThermoFisher Scientific, Logan, Utah), 100 U/mL penicillin, 100 μg/mLstreptomycin, 2-4 mM L-glutamine, and 500 mg/mL G418. For natural,non-recombinant cell lines, the selective antibiotic was omitted, andadditional media formulations can be applied as needed.

Assay Buffer:

The assay buffer was formulated by removing 120 mL from a 1 L bottle offresh, sterile dH₂O (Mediatech, Herndon, Va.) and adding 100 mL of10×HBSS that does not contain Ca⁺⁺ or Mg⁺⁺ (Gibco, Invitrogen, GrandIsland, N.Y.) followed by 20 mL of 1.0 M Hepes, pH 7.3 (FisherScientific, BP299-100). The final buffer consisted of 20 mM Hepes, pH7.3, 1.261 mM CaCl₂, 0.493 mM MgCl₂, 0.407 mM Mg(SO)₄, 5.33 mM KCl,0.441 mM KH₂PO₄, 137 mM NaCl, 0.336 mM Na₂HPO4 and 0.556 mM D-glucose(Hanks et al., Proc. Soc. Exp. Biol. Med. 71:196 (1949)), and the simpleformulation was typically the basic buffer throughout the assay (i.e.,all wash and addition steps).

CoroNa™ Green AM Na⁺ Dye for Primary Fluorescence Assay:

The fluorescence indicator used in the primary fluorescence assay wasthe cell permeant version of CoroNa™ Green (Invitrogen, MolecularProbes, Eugene, Oreg.), a dye that emits light in the fluorescence range(Harootunian et al., J. Biol. Chem. 264(32):19458-19467 (1989)). Theintensity of this emission, but not the wavelength range, is increasedwhen the dye is exposed to Na⁺ ions, which it can bind with partialselectivity. Cells expressing Na_(v)1.7 or other sodium channels wereloaded with the CoroNa™ Green dye immediately in advance of thefluorescence assay, and then, after agonist stimulation, themobilization of Na⁺ ions was detected as the Na⁺ ions flowed from theextracellular fluid into the cytoplasm through the activated sodiumchannel pores. The dye was stored in the dark as a lyophilized powder,and then an aliquot was dissolved immediately before the cell loadingprocedure, according to the instructions of the manufacturer to a stockconcentration of 10 mM in DMSO. It was then diluted in the assay bufferto a 4× concentrated working solution, so that the final concentrationof dye in the cell loading buffer was 5 μM.

Membrane Potential Dye for Alternative Fluorescence Assays:

A fluorescence indicator that can be used in alternative fluorescenceassays is the blue version membrane potential dye (MDS, MolecularDevices, Sunnyvale, Calif.), a dye that detects changes in moleculesfollowing a change in membrane potential. An increase in fluorescence isexpected if agonist stimulation provokes a change in membrane potential.Cells expressing Na_(v)1.7 or other sodium channels are incubated withthe membrane potential dye 30-60 minutes before the fluorescence assay.In the case of the KCl pre-stimulation version of the assay, the dye andall other components are washed out immediately before the assay, andthe dye is then replaced. In the version lacking KCl pre-stimulation,the dye remains on the cells and is not washed out or replaced. The dyeis stored in the dark as a lyophilized powder, and then an aliquotdissolved in assay buffer to form a 20×-concentrated stock solution thatcan be used for several weeks.

Agonists:

In the fluorescence assays, two agonists were used in combination,namely 1) veratridine; and 2) the venom from the yellow scorpion,Leiurus quinquestriatus hebraeus. Veratridine is an alkaloid smallmolecule that facilitates the capture of channel openings by inhibitinginactivation, and the scorpion venom is a natural preparation thatincludes peptide toxins selective for different subsets of voltage-gatedsodium channels. These scorpion toxins inhibit the fast inactivation oftheir cognate target channels. Stock solutions of the agonists wereprepared to 40 mM in DMSO (veratridine) and 1 mg/mL in dH₂O (scorpionvenom), and then diluted to make a 4× or 2× stock (depending on theparticular assay) in assay buffer, the final concentration being 100 μM(veratridine) and 10 μg/mL (scorpion venom). Both of the agonists werepurchased from Sigma Aldrich, St. Louis, Mo.

Test Compounds:

Test compounds were dissolved in DMSO to yield 10 mM stock solutions.The stock solutions were further diluted using DMSO in 1:3 serialdilution steps with 10 points (10,000 μM, 3,333 μM, 1.11 μM, 370 μM, 123μM, 41 μM, 14 μM, 4.6 μM, 1.5 μM and 0.5 μM). The stock solutions werefurther diluted in assay buffer (1:125) as 4× stock serial dilutionswith a DMSO concentration of 0.8% (final [DMSO], in the assay, from thecompounds component=0.2%), so that the compounds' final concentrationsin the assay were 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM and 0.08 μM,0.03 μM, 0.01 μM, 0.003 μM and 0.001 μM. If a particular test articleappeared to be especially potent, then the concentration curve wasadjusted, e.g., to 10-fold lower concentrations, in order to perform thedose-response in a more relevant concentration range. Compound dilutionswere added during the dye-loading and pre-stimulation step, and thenagain during the fluorescence assay, early in the kinetic read. Compounddilutions were added in duplicate rows across the middle 80 wells of the96-well plate, whereas the fully stimulated and the fully inhibitedcontrols (positive and negative) were located in the top 4 side wellsand the bottom 4 side wells, respectively, on the left and right sidesof the assay plate.

Data Analysis:

The data were analyzed according to methods known to those skilled inthe art or using the GraphPad® Prism 4.0 Program (available fromGraphPad Software, San Diego, Calif.) to determine the IC₅₀ value forthe test article. At least one standard reference compound was evaluatedduring each experiment.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay with KCl and Test ArticlePre-Incubation:

Cells were prepared by plating the recombinant HEK293 cells or otherhost cells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate was then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure was very similar, though optimaldensities of cells, media and subsequent assay components can befine-tuned for the particular cell line or isoform.

The next day, at the start of the assay, the media was flicked from thecells and the wells were washed once with 50 μL/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles,CoroNa™ Green AM sodium dye (for cell loading) and KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents were added as follows, immediately after the wash step: 1)First, the compound dilutions and controls were added as 4× concentratesin assay buffer at 50 μL/well; 2) CoroNa™ Green AM dye was diluted fromthe stock solution to 20 μM in assay buffer (4× concentrate) and addedto the plate at 50 μL/well; and 3) Finally, a solution of 180 mM KCl(2×) was prepared by diluting a 2M stock solution into assay buffer andthe solution was added to the cells at 100 μL/well. The cells wereincubated at 25° C. in the dark for 30 min. before their fluorescencewas measured.

The plates containing dye-loaded cells were then flicked to remove thepre-incubation components and washed once with 100 μL/well assay buffer.A 100 μL/well aliquot of assay buffer was added back to the plate, andthe real-time assay was commenced. The fluorescence of cells wasmeasured using a fluorescence plate reader (FLIPR^(TETRA)® or FLIPR384®,MDS, Molecular Devices, Sunnyvale, Calif.) Samples were excited byeither a laser or a PMT light source (Excitation wavelength=470-495 nM)and the emissions are filtered (Emission wavelength=515-575 nM). Theadditions of compound and the channel activators in this cell-based,medium-to-high throughput assay were performed on the fluorescence platereader and the results (expressed as relative fluorescence units) werecaptured by means of camera shots every 1-3 sec., then displayed inreal-time and stored. Generally, there was a 15 sec. base line, withcamera shots taken every 1.5 sec., then the test compounds were added,then another 120 sec. baseline was conducted, with camera shots takenevery 3 sec.; and finally, the agonist solution (containing veratridineand scorpion venom) was added. The amplitude of fluorescence increase,resulting from the binding of Na⁺ ions to the CoroNa™ Green dye, wascaptured for ˜180 sec. thereafter. Results were expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole agonist stimulation period; or by takingthe area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen were typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Membrane Potential Assay with KCl and TestArticle Pre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay (see, e.g., Benjamin et. al., J. Biomol.Screen 10(4):365-373 (2005)). For screens and counter-screens of othervoltage-gated sodium channels, the assay protocol is similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or sodium channel isoform beingtested.

The next day, at the start of the assay, the media is flicked from thecells and the wells are washed once with 50 L/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, themembrane potential dye (for cell loading), and the KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents are added as follows, immediately after the wash step: 1)First, the compound dilutions and controls are added as 4× concentratesin assay buffer at 50 μL/well; 2) Membrane potential dye is diluted fromthe stock solution in assay buffer (4× concentrate) and added to theplate at 50 μL/well; and 3) Finally, a solution of 180 mM KCl (2×) areprepared by diluting a 2M stock solution into assay buffer and thesolution added to the cells at 100 μL/well. The cells are incubated at37° C. in the dark for 30-60 min. before their fluorescence is measured.

The plates containing dye-loaded cells are then flicked to remove thepre-incubation components and washed once with 50 μL/well assay buffer.A 50 μL/well aliquot of membrane potential dye is added back to theplate, and the real-time assay is commenced. The fluorescence of cellsis measured using a fluorescence plate reader (FLIPR^(TETRA)® orFLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.). Samples areexcited by either a laser or a PMT light source (Excitationwavelength=510-545 nM) and the emissions are filtered (Emissionwavelength=565-625 nM). The additions of the compounds (first) and thenthe channel activators (later) in this are performed on the fluorescenceplate reader and the results, expressed as relative fluorescence units(RFU), are captured by means of camera shots every 1-3 sec., thendisplayed in real-time and stored. Generally, there is a 15 sec. baseline, with camera shots taken every 1.5 sec., then the test compoundsare added, then another 120 sec. baseline is conducted, with camerashots taken every 3 sec.; and finally, the agonist solution (containingveratridine and scorpion venom) is added. The amplitude of fluorescenceincrease, resulting from the detection of membrane potential change, iscaptured for ˜120 sec. thereafter. Results are expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole stimulation period; or by taking the areaunder the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay without KCl and Test ArticlePre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure is very similar, though optimal densitiesof cells, media and subsequent assay components can be fine-tuned forthe particular cell line or isoform.

The next day, at the start of the assay, the media is flicked from thecells and the wells washed once with 50 μL/well assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3). Membrane potential dye is then added to each well of the96-well plate (50 μL/well), from a freshly diluted sample of the stock(now at 4× concentration) in the assay buffer. The cells are incubatedat 37° C. in the dark for 30-60 min. before their fluorescence ismeasured.

In this standard membrane potential assay, the 96-well plate containingdye-loaded cells is then loaded directly onto the plate reader withoutaspirating the dye solution and without any further washing of thecells. The fluorescence of cells is measured using a fluorescence platereader (FLIPR^(TETRA)® Or FLIPR384®, MDS, Molecular Devices, Sunnyvale,Calif.). Samples are excited by either a laser or a PMT light source(Excitation wavelength=510-545 nM) and the emissions are filtered(Emission wavelength=565-625 nM). The additions of the compounds (first,50 μL/well from a 4× stock plate) and then the channel activators(later, 100 μL/well from a 2× stock solution) in this kinetic assay areperformed on the fluorescence plate reader and the results, expressed asrelative fluorescence units (RFU), are captured by means of camera shotsevery 1-3 sec., then displayed in real-time and stored. Generally, thereis a 15 sec. base line, with camera shots taken every 1.5 sec., then thetest compounds are added, then another 120 sec. baseline is conducted,with camera shots taken every 3 sec.; and finally, the agonist solution(containing veratridine and scorpion venom) is added. The amplitude offluorescence increase, resulting from the detection of membranepotential change, is captured for ˜120 sec. thereafter. Results areexpressed in relative fluorescence units (RFU) and can be determined byusing the maximum signal during the latter part of the stimulation; orthe maximum minus the minimum during the whole stimulation period; or bytaking the area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well, with the testarticles present in standard amounts (e.g. 1 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

Electrophysiology Assay

Cells:

The hNa_(v)1.7 expressing HEK-293 cells were plated on 35 mm culturedishes pre-coated with poly-D-lysine in standard DMEM culture media(Mediatech, Inc., Herndon, Va.) and incubated in a 5% CO₂ incubator at37° C. Cultured cells were used approximately 12-48 hours after plating.

Electrophysiology:

On the day of experimentation, the 35 mm dish was placed on the stage ofan inverted microscope equipped with a perfusion system thatcontinuously perfuses the culture dish with fresh recording media. Agravity driven superfusion system was used to apply test solutionsdirectly to the cell under evaluation. This system consists of an arrayof glass pipette glass connected to a motorized horizontal translator.The outlet of the shooter was positioned approximately 100 jtm from thecell of interest.

Whole cell currents were recorded using the whole-cell patch clampconfiguration using an Axopatch 200B amplifier (Axon Instruments, FosterCity Calif.), 1322A A/D converter (Axon Instruments) and pClamp software(v. 8; Axon Instruments) and stored on a personal computer. Gigasealswere formed and the whole-cell configuration was established in voltageclamp mode, and membrane currents generated by hNa_(v)1.7 were recordedin gap-free mode. Borosilicate glass pipettes have resistance valuesbetween 1.5 and 2.0 MΩ when filled with pipette solution and seriesresistance (<5 MR) was compensated 75-80%. Signals were sampled at 50kHz and low pass filtered at 3 kHz.

The voltage clamp protocol to examine hNa_(v)1.7 currents was asfollows. First, the standard current-voltage relationship was tested bypulsing the cell from the holding voltage (V_(h)) of ˜120 mV by a seriesof 5 msec long square-shaped test pulses incrementing in +10 mV stepsover the membrane voltage range of −90 mV to +60 mV at the pace ofstimulation of 0.5 Hz. This procedure determines the voltage thatelicits the maximal current (V_(max)). Second, V_(h) was re-set to −120mV and a steady-state inactivation (SSIN) curve was taken by thestandard double-pulse protocol: 100 ms depolarizing pre-pulse wasincremented in steps of +10 mV (voltage range from −90 mV to 0 mV)immediately followed by the 5 ms long test pulse to −10 mV at the paceof stimulation of 0.2 Hz. This procedure determines the voltage of fullinactivation (V_(full)). Third, the cell was repeatedly stimulated withthe following protocol, first in the absence of the test compound thenin its presence. The protocol consisted of depolarizing the cell fromthe holding potential of −120 mV to the V_(full) value for 4.5 secondsthen repolarizing the cell to the holding potential for 10 ms beforeapplying the test pulse to the V_(max) for 5 ms. The amount ofinhibition produced by the test compound was determined by comparing thecurrent amplitude elicited by the test pulse in the absence and presenceof the compound.

Solutions and Chemicals:

For electrophysiological recordings the external solution was eitherstandard, DMEM supplemented with 10 mM HEPES (pH adjusted to 7.34 withNaOH and the osmolarity adjusted to 320) or Tyrodes salt solution(Sigma, USA) supplemented with 10 mM HEPES (pH adjusted to 7.4 withNaOH; osmolarity=320). The internal pipette solution contained (in mM):NaCl (10), CsF (140), CaCl₂ (1), MgCl₂ (5), EGTA (11), HEPES (10: pH7.4, 305 mOsm). Compounds were prepared first as series of stocksolutions in DMSO and then dissolved in external solution; DMSO contentin final dilutions did not exceed 0.3%. At this concentration, DMSO didnot affect sodium currents. Vehicle solution used to establish base linewas also contacting 0.3% DMSO.

Data Analysis:

Data was analyzed off-line using Clampfit software (pClamp, v. 8; AxonInstruments) and graphed using GraphPad Prizm (v. 4.0) software.

In Vivo Assay for Pain

The compounds of the present invention can be tested for theirantinociceptive activity in the formalin model as described in Hunskaaret al., J. Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIHmice (20-30 g; Harlan, San Diego, Calif.) can be used in allexperiments. Food is withdrawn on the day of experiment. Mice are placedin Plexiglass jars for at least 1 hour to acclimate to the environment.Following the acclimation period mice are weighed and given either thecompound of interest administered i.p. or p.o., or the appropriatevolume of vehicle (for example, 10% Tween-80 or 0.9% saline, and otherpharmaceutically acceptable vehicles) as control. Fifteen minutes afterthe i.p. dosing, and 30 minutes after the p.o. dosing mice are injectedwith formalin (20 μL of 5% formaldehyde solution in saline) into thedorsal surface of the right hind paw. Mice are transferred to thePlexiglass jars and monitored for the amount of time spent licking orbiting the injected paw. Periods of licking and biting are recorded in5-minute intervals for 1 hour after the formalin injection. Allexperiments are done in a blinded manner during the light cycle. Theearly phase of the formalin response is measured as licking/bitingbetween 0-5 minutes, and the late phase is measured from 15-50 minutes.Differences between vehicle and drug treated groups can be analyzed byone-way analysis of variance (ANOVA). A P value <0.05 is consideredsignificant. Compounds are considered to be efficacious for treatingacute and chronic pain if they have activity in blocking both the earlyand second phase of formalin-induced paw-licking activity.

In vivo Assays for Inflammatory or Neuropathic Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a testcompound when food is removed for 16 hours before dosing. A controlgroup acts as a comparison to rats treated with a compound of FormulaeI-XX. The control group is administered the carrier as used for the testcompound. The volume of carrier administered to the control group is thesame as the volume of carrier and test compound administered to the testgroup.

Inflammatory Pain:

To assess the actions of the compounds of Formulae I-XX on the treatmentof inflammatory pain the Freund's complete adjuvant (“FCA”) model ofinflammatory pain is used. FCA-induced inflammation of the rat hind pawis associated with the development of persistent inflammatory mechanicaland thermal hyperalgesia and provides reliable prediction of theanti-hyperalgesic action of clinically useful analgesic drugs (Bartho etal., Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)).The left hind paw of each animal is administered a 50 μL intraplantarinjection of 50% FCA. 24 hour post injection, the animal is assessed forresponse to noxious mechanical stimuli by determining the paw withdrawalthreshold (PWT), or to noxious thermal stimuli by determining the pawwithdrawal latency (PWL), as described below. Rats are then administereda single injection of either a test compound or 30 mg/Kg of a positivecontrol compound (indomethacin). Responses to noxious mechanical orthermal stimuli are then determined 1, 3, 5 and 24 hours postadministration (admin). Percentage reversal of hyperalgesia for eachanimal is defined as:

${\% \mspace{14mu} {reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack} \times 100}$

Neuropathic Pain:

To assess the actions of the test compounds for the treatment ofneuropathic pain the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats(Seltzer et al., Pain 43:205-218 (1990)). Partial ligation of the leftsciatic nerve is performed under isoflurane/O₂ inhalation anaesthesia.Following induction of anaesthesia, the left thigh of the rat is shavedand the sciatic nerve exposed at high thigh level through a smallincision and is carefully cleared of surrounding connective tissues at asite near the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture is inserted into the nerve with a 3/8 curved,reversed-cutting mini-needle and tightly ligated so that the dorsal 1/3to 1₂ of the nerve thickness is held within the ligature. The wound isclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. Following surgery, the wound area is dusted with antibioticpowder. Sham-treated rats undergo an identical surgical procedure exceptthat the sciatic nerve is not manipulated. Following surgery, animalsare weighed and placed on a warm pad until they recover fromanaesthesia. Animals are then returned to their home cages untilbehavioral testing begins. The animals are assessed for response tonoxious mechanical stimuli by determining PWT, as described below, priorto surgery (baseline), then immediately prior to and 1, 3, and 5 hoursafter drug administration for rear paw of the animal. Percentagereversal of neuropathic hyperalgesia is defined as:

${\% \mspace{14mu} {reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painwas used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery was performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia a 3 cmincision was made and the left paraspinal muscles were separated fromthe spinous process at the L₄-S₂ levels. The L₆ transverse process wascarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) was(were) isolated and tightly ligated with silk thread. A completehemostasis was confirmed and the wound was sutured using non-absorbablesutures, such as nylon sutures or stainless steel staples. Sham-treatedrats underwent an identical surgical procedure except that the spinalnerve(s) was (were) not manipulated. Following surgery animals wereweighed, administered a subcutaneous (s.c.) injection of saline orringers lactate, the wound area was dusted with antibiotic powder andthey were kept on a warm pad until they recovered from the anaesthesia.Animals were then returned to their home cages until behavioral testingbegins. The animals were assessed for response to noxious mechanicalstimuli by determining PWT, as described below, prior to surgery(baseline), then immediately prior to and 1, 3, and 5 hours after beingadministered a compound of Formulae I-XX for the left rear paw of theanimal. The animals can also be assessed for response to noxious thermalstimuli or for tactile allodynia, as described below. The Chung modelfor neuropathic pain is described in Kim et al., Pain 50(3):355-363(1992).

Tactile Allodynia: Sensitivity to non-noxious mechanical stimuli can bemeasured in animals to assess tactile allodynia. Rats are transferred toan elevated testing cage with a wire mesh floor and allowed to acclimatefor five to ten minutes. A series of von Frey monofilaments are appliedto the plantar surface of the hindpaw to determine the animal'swithdrawal threshold. The first filament used possesses a bucklingweight of 9.1 gms (0.96 log value) and is applied up to five times tosee if it elicits a withdrawal response. If the animal has a withdrawalresponse, then the next lightest filament in the series would be appliedup to five times to determine if it also could elicit a response. Thisprocedure is repeated with subsequent lesser filaments until there is noresponse and the identity of the lightest filament that elicits aresponse is recorded. If the animal does not have a withdrawal responsefrom the initial 9.1 gms filament, then subsequent filaments ofincreased weight are applied until a filament elicits a response and theidentity of this filament is recorded. For each animal, threemeasurements are made at every time point to produce an averagewithdrawal threshold determination. Tests can be performed prior to, andat 1, 2, 4 and 24 hours post drug administration.

Mechanical Hyperalgesia:

Sensitivity to noxious mechanical stimuli can be measured in animalsusing the paw pressure test to assess mechanical hyperalgesia. In rats,hind paw withdrawal thresholds (“PWT”), measured in grams, in responseto a noxious mechanical stimulus are determined using an analgesymeter(Model 7200, commercially available from Ugo Basile of Italy), asdescribed in Stein (Biochemistry & Behavior 31: 451-455 (1988)). Therat's paw is placed on a small platform, and weight is applied in agraded manner up to a maximum of 250 grams. The endpoint is taken as theweight at which the paw is completely withdrawn. PWT is determined oncefor each rat at each time point. PWT can be measured only in the injuredpaw, or in both the injured and non-injured paw. In one non-limitingembodiment, mechanical hyperalgesia associated with nerve injury inducedpain (neuropathic pain) can be assessed in rats. Rats are tested priorto surgery to determine a baseline, or normal, PWT. Rats are testedagain 2 to 3 weeks post-surgery, prior to, and at different times after(e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWTfollowing drug administration indicates that the test compound reducesmechanical hyperalgesia.

Some compounds of the present invention significantly reduced mechanicalhyperalgesia in the spinal nerve ligation (SNL; Chung model ofneuropathic pain). For example, compounds 47 and 60 induced 10%-25%reversal of mechanical hyperalgesia from 1 to 3 hours followingintraperitoneal (i.p.) administration.

In vivo Assay for Anticonvulsant Activity

The compounds of the present invention can be tested for in vivoanticonvulsant activity after i.v., p.o., or i.p. injection using any ofa number of anticonvulsant tests in mice, including the maximumelectroshock seizure test (MES). Maximum electroshock seizures areinduced in male NSA mice weighing between 15-20 g and in maleSprague-Dawley rats weighing between 200-225 g by application of current(for mice: 50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration,D.C.; for rats: 99 mA, 125 pulses/sec, 0.8 msec pulse width, 2 secduration, D.C.) using a Ugo Basile ECT device (Model 7801). Mice arerestrained by gripping the loose skin on their dorsal surface andsaline-coated corneal electrodes are held lightly against the twocorneae. Rats are allowed free movement on the bench top and ear-clipelectrodes are used. Current is applied and animals are observed for aperiod of up to 30 seconds for the occurrence of a tonic hindlimbextensor response. A tonic seizure is defined as a hindlimb extension inexcess of 90 degrees from the plane of the body. Results can be treatedin a quantal manner.

Pharmaceutical Compositions

Although a compound of the present invention may be administered to amammal in the form of a raw chemical without any other componentspresent, the compound is preferably administered as part of apharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the present inventioninclude all compositions where a compound of the present invention iscombined with a pharmaceutically acceptable carrier. In a preferredembodiment, the compound is present in the composition in an amount thatis effective to achieve its intended therapeutic purpose. Whileindividual needs may vary, a determination of optimal ranges ofeffective amounts of each compound is within the skill of the art.Typically, the compounds may be administered to a mammal, e.g., a human,orally at a dose of from about 0.0025 to about 1500 mg per kg bodyweight of the mammal, or an equivalent amount of a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, per day to treat, preventor ameliorate the particular disorder. A useful oral dose of a compoundof the present invention administered to a mammal is from about 0.0025to about 50 mg per kg body weight of the mammal, or an equivalent amountof the pharmaceutically acceptable salt, prodrug, or solvate thereof.For intramuscular injection, the dose is typically about one-half of theoral dose.

A unit oral dose may comprise from about 0.01 to about 50 mg, andpreferably about 0.1 to about 10 mg, of the compound. The unit dose canbe administered one or more times daily, e.g., as one or more tablets orcapsules, each containing from about 0.01 to about 50 mg of thecompound, or an equivalent amount of a pharmaceutically acceptable salt,prodrug or solvate thereof.

A pharmaceutical composition of the present invention can beadministered to any animal that may experience the beneficial effects ofa compound of the present invention. Foremost among such animals aremammals, e.g., humans and companion animals, although the invention isnot intended to be so limited.

A pharmaceutical composition of the present invention can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, health, and weight of the recipient,condition or disorder to be treated, kind of concurrent treatment, ifany, frequency of treatment, and the nature of the effect desired.

In one embodiment, a pharmaceutical composition of the present inventioncan be administered orally and is formulated into tablets, dragees,capsules or an oral liquid preparation. In one embodiment, the oralformulation comprises extruded multiparticulates comprising the compoundof the invention.

Alternatively, a pharmaceutical composition of the present invention canbe administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present invention canbe administered by injection.

Alternatively, a pharmaceutical composition of the present invention canbe administered transdermally.

Alternatively, a pharmaceutical composition of the present invention canbe administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present invention canbe administered by the intravaginal route.

A pharmaceutical composition of the present invention can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present invention, such as a method for treating adisorder responsive to the blockade of sodium channels in an animal inneed thereof, can further comprise administering a second therapeuticagent to the animal in combination with a compound of the presentinvention. In one embodiment, the other therapeutic agent isadministered in an effective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

A compound of the present invention (i.e., the first therapeutic agent)and the second therapeutic agent can act additively or, in oneembodiment, synergistically. Alternatively, the second therapeutic agentcan be used to treat a disorder or condition that is different from thedisorder or condition for which the first therapeutic agent is beingadministered, and which disorder or condition may or may not be acondition or disorder as defined herein. In one embodiment, a compoundof the present invention is administered concurrently with a secondtherapeutic agent; for example, a single composition comprising both aneffective amount of a compound of any of Formulae I-XX, and an effectiveamount of the second therapeutic agent can be administered. Accordingly,the present invention further provides a pharmaceutical compositioncomprising a combination of a compound of the present invention, thesecond therapeutic agent, and a pharmaceutically acceptable carrier.Alternatively, a first pharmaceutical composition comprising aneffective amount of a compound of any of Formulae I-XX and a secondpharmaceutical composition comprising an effective amount of the secondtherapeutic agent can be concurrently administered. In anotherembodiment, an effective amount of a compound of the present inventionis administered prior or subsequent to administration of an effectiveamount of the second therapeutic agent. In this embodiment, the compoundof the present invention is administered while the second therapeuticagent exerts its therapeutic effect, or the second therapeutic agent isadministered while the compound of the present invention exerts itstherapeutic effect for treating a disorder or condition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine; alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof.Examples of other suitable non-opioid analgesics include the following,non limiting, chemical classes of analgesic, antipyretic, nonsteroidalantiinflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; paraaminophennol derivatives including acetaminophen and phenacetin; indoleand indene acetic acids, including indomethacin, sulindac, and etodolac;heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac;anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R.Hanson, Analgesic, Antipyretic and Anti Inflammatory Drugs in Remington:The Science and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed.19th ed. 1995) which are hereby incorporated by reference in theirentireties. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, and cisplatin.

Therapeutic agents useful for treating an addictive disorder include,but are not limited to, methadone, desipramine, amantadine, fluoxetine,buprenorphine, an opiate agonist, 3-phenoxypyridine, or a serotoninantagonist.

Examples of useful therapeutic agents for treating Parkinson's diseaseand parkinsonism include, but are not limited to, carbidopa/levodopa,pergolide, bromocriptine, ropinirole, pramipexole, entacapone,tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride.

Examples of useful therapeutic agents for treating anxiety include, butare not limited to, benzodiazepines, such as alprazolam, brotizolam,chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam,diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam,midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam,temazepam, and triazolam; non-benzodiazepine agents, such as buspirone,gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon;tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital,butabarbital, butalbital, mephobarbital, methohexital, pentobarbital,phenobarbital, secobarbital, and thiopental; and propanediol carbamates,such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating epilepsy or seizureinclude, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproicacid, trimethadione, benzodiazepines, gamma-vinyl GABA, acetazolamide,and felbamate.

Examples of useful therapeutic agents for treating stroke include, butare not limited to, anticoagulants such as heparin, agents that break upclots such as streptokinase or tissue plasminogen activator, agents thatreduce swelling such as mannitol or corticosteroids, and acetylsalicylicacid.

Examples of useful therapeutic agents for treating a pruritic conditioninclude, but are not limited to, naltrexone; nalmefene; danazol;tricyclics such as amitriptyline, imipramine, and doxepin;antidepressants such as those given below; menthol; camphor; phenol;pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating psychosis include,but are not limited to, phenothiazines such as chlorpromazinehydrochloride, mesoridazine besylate, and thoridazine hydrochloride;thioxanthenes such as chloroprothixene and thiothixene hydrochloride;clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate;haloperidol; haloperidol decanoate; loxapine succinate; molindonehydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating ALS include, but arenot limited to, baclofen, neurotrophic factors, riluzole, tizanidine,benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating cognitive disordersinclude, but are not limited to, agents for treating or preventingdementia such as tacrine; donepezil; ibuprofen; antipsychotic drugs suchas thioridazine and haloperidol; and antidepressant drugs such as thosegiven below.

Examples of useful therapeutic agents for treating a migraine include,but are not limited to, sumatriptan; methysergide; ergotamine; caffeine;and beta-blockers such as propranolol, verapamil, and divalproex.

Examples of useful therapeutic agents for treating vomiting include, butare not limited to, 5-HT3 receptor antagonists such as ondansetron,dolasetron, granisetron, and tropisetron; dopamine receptor antagonistssuch as prochlorperazine, thiethylperazine, chlorpromazine,metoclopramide, and domperidone; glucocorticoids such as dexamethasone;and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating dyskinesia include,but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating depression include,but are not limited to, tricyclic antidepressants such as amitryptyline,amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine,maprotiline, nefazadone, nortriptyline, protriptyline, trazodone,trimipramine, and venlafaxine; selective serotonin reuptake inhibitorssuch as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine,and setraline; monoamine oxidase inhibitors such as isocarboxazid,pargyline, phenelzine, and tranylcypromine; and psychostimulants such asdextroamphetamine and methylphenidate.

A pharmaceutical composition of the present invention is preferablymanufactured in a manner which itself will be known in view of theinstant disclosure, for example, by means of conventional mixing,granulating, dragee-making, dissolving, extrusion, or lyophilizingprocesses. Thus, pharmaceutical compositions for oral use can beobtained by combining the active compound with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate can be used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which may bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers may be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound may be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the present invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the invention.

EXAMPLES Example 1

(a) 2-Nitro-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethylester (6) was prepared as follows. A mixture of compound 1 (1 g, 5.2mmol, 1.0 eq, Aldrich), compound 2 (1.2 g, 5.6 mmol, Aldrich), K₂CO₃(2.6 g, 18 mmol), bis(triphenylphosphine)palladium(II) chloride(Aldrich, 0.1 eq), water (0.1 mL) and EtOH (40 mL) in a 250 mL flask wasflushed with argon, and heated to 60° C. for 18 hours. The reactionmixture was filtered, concentrated, and then suspended with water (100mL), and extracted with CHCl₃ (2×100 mL). The organic layers werecombined, concentrated and purified by column (Silica gel, CHCl₃/hexanes½) to afford compound 3 as a brown solid (1 g, 67%): LC/MS: m/z=286[M+H]⁺ (Calc: 285).

(b) A mixture of compound 3 (2 g, 7 mmol), compound 5 (1.5 eq, 37%aqueous solution), CH₂(NO₂)CO₂Et (4, 1.2 eq, Aldrich) and AcOH (3.0 eq)in 10 mL 1,4-dioxane was shaken at 78° C. for 14 hours. The solvent wasremoved under vacuum. The residue was suspended in CHCl₃ (30 mL), andneutralized with saturated NaHCO₃ aqueous to pH˜8. The organic layer wasseparated, concentrated and purified by column (Silica gel,CHCl₃/hexanes, then, CHCl₃/MeOH 10/0.2) to get2-nitro-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester(6) as white solid (1.8 g, 60%): ¹H-NMR (400 MHz, CDCl₃) δ: 8.1 (s, 1H),7.72 (s, 1H), 7.58-7.63 (m, 2H), 7.34-7.46 (m, 4H), 7.05-7.15 (m, 6H),5.45 (dd, 1H, 5.7 & 5.6 Hz), 4.26-4.32 (m, 2H), 3.68-3.82 (m, 2H), 1.28(t, 3H, 7.1 Hz).

(c) 2-Amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethylester (7) was prepared as follows. Compound 6 (0.5 g) was dissolved in amixture of CHCl₃ (5 mL) and EtOH (15 mL). Palladium on carbon (10% wet,0.25 g) was added to this solution, and shaken under hydrogen (50 PSI)for 24 hours at room temperature. After filtration over Celite, HCl (4Nin 1,4-dioxane, 2 mL) was added to the mixture. The solvents wereevaporated under vacuum to afford2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester(7) as a white solid (0.4 g, 80%): ¹H-NMR (400 MHz, CD₃OD) δ: 7.75 (s,1H), 7.65-7.71 (m, 2H), 7.35-7.51 (m, 4H), 7.05-7.15 (m, 5H), 0.4.2-4.4(m, 3H), 3.4-3.5 (m, 2H), 1.2 (t, 3H, 7.2 Hz); LC/MS: m/z=401.5 [M+H]⁺(Calc: 400.5).

Example 2

(a) 2-Amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide (8) wasprepared as follows. A mixture of compound 7 prepared in Example 1 (0.2g), NH₃ (7N in MeOH, 6 mL) was shaken at 70° C. for 36 hours. EtOAc (40mL) was added to the reaction mixture, then, washed with water andbrine, concentrated and purified by column (EtOAc/MeOH 10/1, thenEtOAc/MeOH/NH₄OH 10/2/0.5) to afford compound 8 as a yellow solid (0.11g, 64%): ¹H-NMR (400 MHz, CD₃OD) δ: 7.85 (s, 1H), 7.68-7.72 (m, 2H),7.35-7.41 (m, 4H), 7.02-7.15 (m, 5H), 3.74-3.78 (m, 1H), 3.25-3.3 (m,1H), 3.04-3.14 (m, 1H); LC/MS: m/z=372.5 [M+H]⁺ (Calc: 371.4).

(b) 2-Amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid (9) wasprepared as follows: NaOH (2N aqueous, 1 mL) was added to a solution ofcompound 7 prepared in Example 1 (0.2 g) in MeOH (4 mL) at 0° C. Thereaction mixture was shaken at 30° C. for 24 hours. The solvents wereevaporated under vacuum. The residues were dissolved in CHCl₃ (40 mL)and neutralized to pH˜2 with 1N HCl aqueous. The organic layer wasseparated, washed with brine and concentrated to get a sticky oil, whichwas washed with Et₂O, and dried under vacuum to afford compound 9 as aHCl-salt (white solid, 70 mg, 35%): ¹H-NMR (400 MHz, CD₃OD) &: 7.88 (s,1H), 7.58-7.72 (m, 2H), 7.25-7.41 (m, 4H), 6.88-7.05 (m, 5H), 3.47-3.72(m, 1H), 3.25-3.28 (m, 1H), 2.81-2.88 (m, 1H); LC/MS: m/z=358 [M+H]⁺(Calc: 372.4).

Example 3

2-Amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol (10) wasprepared as follows: A mixture compound 7 prepared in Example 1 (0.2 g,1.0 eq) and NaBH₄ (4 eq) in 10 mL EtOH was shaken at room temperaturefor 72 hours. The solvent was removed under vacuum, then, water (10 mL)and EtOAc (40 mL) was added to it. The organic layer was separated,concentrated and purified by column (Silica gel, EtOAc/MeOH 10/1, thenEtOAc/MeOH/NH₄OH 10/2/0.2) to get compound 10 as a yellow solid (60 mg,38%): ¹H-NMR (400 MHz, CD₃OD) δ: 7.76 (s, 1H), 7.6-7.65 (m, 2H),7.32-7.46 (m, 4H), 7.16 (s, 1H), 7.02-7.12 (m, 5H), 3.74-3.78 (m, 1H),3.55-3.6 (m, 1H), 3.4-3.46 (m, 1H), 3.06-3.12 (m, 1H), 2.96-3.02 (m,1H); LC/MS: m/z=359.4 [M+H]⁺ (Calc: 358.4).

Example 4

2-Nitro-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester(13) and 2-amino-3-[6-(4-phenoxy-phenyl)-1H-indol-3-yl]-propionic acidethyl ester (14) were prepared according to the procedure described inExample 1 using compound 11 (Combi-Blocks) as a starting materialinstead of compound 1. Compound 13 (HCl-salt) LC/MS: m/z=431.5 [M+H]⁺(Calc. 430.5). Compound 14 (HCl-salt) LC/MS: m/z=401.5 [M+H]⁺ (Calc:400.5).

Example 5

(a) 2-Amino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide (15) wasprepared as follows: A mixture of compound 14 prepared in Example 4 (0.2g) and NH₃ (7N in MeOH, 6 mL, and 28% aqueous, 2 mL) was shaken at 70°C. for 16 hours. EtOAc (40 mL) and water (10 mL) were added to thereaction mixture. The organic layer was separated, concentrated andpurified by column (EtOAc/MeOH 10/1, then EtOAc/MeOH/NH₄OH 10/2/0.5) toafford compound 15 as a brown solid (0.1 g, 53%): ¹H-NMR (400 MHz,CD₃OD) δ: 7.6 (d, 1H, 8.3 Hz), 7.46-7.55 (m, 3H), 7.18-7.28 (m, 3H),7.06 (s, 1H), 6.92-7.05 (m, 5H), 3.58-3.62 (m, 1H), 3.1-3.15 (m, 1H),2.88-2.94 (m, 1H); LC/MS: m/z=372.1 [M+H]⁺ (Calc: 371.4).

(b)2-tert-Butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]-propionicacid ethyl ester (16) was prepared as follows: Triethylamine (0.15, 3.5eq, TEA) was added to a solution of compound 14 prepared in Example 4(0.2 g, 0.4 mmol) and di-tert-butyl dicarbonate (0.14 g, 1.5 eq) in 5 mLof chloroform at 0° C., and then the reaction mixture was warmed to 30°C. and shaken at 30° C. for 20 hours. Water was added to the reactionmixture and the organic layer was separated, and purified by column(Silica gel, CHCl₃/MeOH 10/1) to afford compound 16 as a white solid(190 mg, 90%): ¹H-NMR (400 MHz, CDCl₃) δ: 8.14 (s, 1H), 7.6-7.65 (m,3H), 7.55 (s, 1H), 7.36-7.41 (m, 3H), 6.98-7.15 (m, 6H), 5.1-5.14 (m,1H), 4.64-4.68 (m, 1H), 4.14-4.18 (m, 2H), 3.3-3.34 (m, 2H), 1.44 (s,9H), 1.24 (t, 3H, 7.2 Hz); LC/MS: m/z=523.5 [M+Na⁺]⁺ (Calc: 500.6).

(c)2-tert-Butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]-propionicacid (17) was prepared as follows: A mixture of compound 16 (0.1 g in 4mL MeOH) and NaOH (0.5N aqueous, 0.5 mL) was shaken at 30° C. for 24hours. The solvent was removed under vacuum. The residue was suspendedin CHCl₃ (20 mL), neutralized with 0.5N HCl to ˜pH 2, and concentratedto get compound 17 as a white solid (50 mg, 53%): ¹H-NMR (400 MHz,CD₃OD/CDCl₃ 3/1) δ: 7.8-7.84 (m, 3H), 7.75 (s, 1H), 747-7.57 (m, 3H),7.2-7.32 (m, 6H), 4.61-4.65 (m, 1H), 3.51-3.55 (m, 1H), 3.31-3.37 (m,1H), 1.43-1.6 (m, 9H); LC/MS: m/z=495.6 [M+Na⁺]⁺ (Calc: 472.5).

Example 6

2-Amino-3-[7-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol (22) wasprepared using the procedure described in Examples 1, 2 and 3 usingcompound 18 (Combi-Blocks) as starting material instead of compound 1.Compound 22 was obtained a white solid (HCl-salt): ¹H-NMR (400 MHz,CD₃OD) δ: 7.46-7.53 (m, 3H), 7.25-7.3 (m, 2H), 7.14 (s, 1H), 6.95-7.06(m, 7H), 3.66-3.71 (m, 1H), 3.45-3.55 (m, 2H), 3.0-3.06 (m, 2H); LC/MS:m/z=359.5 [M+H]⁺ (Calc: 358.4).

Example 7

(a) 2-Nitro-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethylester (26) was prepared as follows: A mixture of compound 23 (Aldrich, 3g, 14.2 mmol), compound 24 (Aldrich, 2.1 g, 1.05 eq), AcOH (0.1 mL) andEtOH (25 mL) was heated at 80° C. under argon for 4 hours. The solventwas evaporated under vacuum, and polyphosphoric acid (20 g) was added tothe residue. The resulting sticky mixture was stirred at 120° C. for 5hours, and then poured into crushed ice, and then neutralized with 1NNaOH and extracted with DCM (3×30 mL). The organic layers were combined,washed with brine, and concentrated to give compound 25 as a blue solid(2.8 g, 70%): LC/MS: m/z=286.2 [M+H]⁺ (Calc: 285.3).

(b) A mixture of compound 25 (0.2 g, 0.7 mmol), paraformaldehyde(Aldrich, 0.1 g, 5 eq), compound 4 (0.18 g, 2.0 eq) and molecular sieves4 Å (Aldrich, 0.4 g) in toluene (6 mL) was shaken at 95° C. for 2 hours.The mixture was then filtered, washed with CHCl₃ (4 mL) and purified bycolumn (Silica gel, CHCl₃) to get compound 26 (0.1 g, brown oil, 34%):LC/MS: m/z=286.2 [M+H]⁺ (Calc: 285.3), which was dissolved in a mixtureof CHCl₃ (5 mL) and EtOH (10 mL). Palladium on carbon (10% wet, 0.1 g)was added to this solution, and shaken under hydrogen (50 PSI) for 24hours at room temperature. After filtration on Celite, HCl (4N in1,4-dioxane, 2 mL) was added to the mixture. The solvents wereevaporated under vacuum to give intermediate 27 as a brown solid (85 mg,85%): LC/MS: m/z=401.1 [M+H]⁺ (Calc: 400.5).

(c) A mixture of compound 27 (70 mg) and NH₃ (7N in MeOH 4 mL, and 4 mL28% aqueous) was heated under microwave at 110° C. for 2 hours. EtOAc(20 mL) and water (5 mL) were added to the reaction mixture. The organiclayer was separated, concentrated and purified by column (EtOAc/MeOH10/1, then EtOAc/MeOH/NH₄OH 10/2/0.5) to afford a brown oil, which wasdissolved in 0.5N HCl aqueous (20 mL), and freeze dried under vacuum togive compound 28 as a HCl-salt (brown solid, 40 mg, 58%): ¹H-NMR (400MHz, CD₃OD) δ: 7.62-7.73 (m, 3H), 7.39-7.44 (m, 3H), 7.07-7.21 (m, 7H),4.16-4.21 (m, 1H), 3.57-3.58 (m, 1H), 3.35-3.41 (m, 1H); LC/MS:m/z=372.1 [M+H]⁺ (Calc: 371.4).

Example 8

(a) 2-Nitro-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethylester (32) was prepared as follows: A mixture of compound 29 (Aldrich, 1g, 8.5 mmol, 1.0 eq), compound 30a (Aldrich, 1.2 eq), CuI (0.5 eq),K₂CO₃ (3 eq), and dimethylglycine (Aldrich, 0.1 eq) in DMF (10 mL) washeated at 150° C. for 30 minutes under microwave. The mixture wasfiltered, and dissolved in water/EtOAc (20 mL/100 mL). The organic layerwas washed with brine, concentrated and purified by column (silica gel,CHCl₃/hexane 1/10) to afford compound 31 as a white solid (1.8 g, 70%):¹H-NMR (400 MHz, CDCl₃) δ: 7.59-7.62 (m, 1H), 7.42-7.44 (m, 1H),7.28-7.37 (m, 4H), 7.21 (d, 1H, 3.2 Hz), 6.99-7.15 (m, 7H), 6.59 (dd,1H, 0.8 & 3.2 Hz). A mixture of compound 31 (1.5 g, 5.3 mmol), compound5 (3 eq, 37% aqueous solution), CH₂(NO₂)CO₂Et (4, 1.8 eq, Aldrich) andAcOH (5.0 eq) in 10 mL of 1,4-dioxane was shaken at 78° C. for 14 hours.The solvent was removed under vacuum. The residue was suspended in CHCl₃(30 mL), then, neutralized with saturated NaHCO₃ aqueous to pH˜8. Theorganic layer was separated, concentrated and purified by column (Silicagel, CHCl₃/hexanes V2, then, CHCl₃/MeOH 10/0.2) to obtain compound 32 asa brown oil (1.2 g, 50%): %): ¹H-NMR (400 MHz, CDCl₃) δ: 7.66-7.68 (m,1H), 7.51-7.53 (m, 1H), 7.4-7.44 (m, 4H), 7.1-7.3 (m, 8H), 5.51 (dd, 1H,4.8 & 4.9 Hz), 4.32-4.35 (m, 2H), 3.72-3.87 (m, 2H), 1.3-1.35 (m, 3H).

(b) 2-Amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethylester (33) was prepared as follows: Palladium on carbon (10% wet, 0.4 g)was added to a solution of compound 32 (1.2 g) in CHCl₃ (10 mL) and EtOH(30 mL). The reaction mixture was shaken under hydrogen (50 PSI) for 24hours at room temperature. After filtration on Celite, HCl (4N in1,4-dioxane, 4 mL) was added and the solvents were evaporated undervacuum to give compound 33 as a blue solid (1.1 g, 90%): LC/MS:m/z=401.1 [M+H]⁺ (Calc: 400.5).

(c) 2-Amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol (34) wasprepared as follows: A mixture of compound 33 (0.15 g, 1.0 eq) and NaBH₄(4 eq) in 15 mL of EtOH was shaken at room temperature for 72 hours. Thesolvent was removed under vacuum. Water (10 mL) and EtOAc (40 mL) wereadded to the residue. The organic layer was separated, concentrated andpurified by column (Silica gel, EtOAc/MeOH/NH₄OH 10/2/0.2) to get asticky oil, which was dissolved in 25 mL of HCl (0.25N aqueous), then,freeze dried to afford compound 34 as a brown solid (45 mg, 35%): ¹H-NMR(400 MHz, CD₃OD) δ: 7.59 (d, 1H, 7.9 Hz), 7.4-7.44 (m, 3H), 7.28-7.32(m, 3H), 7.04-7.15 (m, 5H), 6.95-6.99 (m, 2H), 3.7-3.74 (m, 1H),3.47-3.58 (m, 2H), 3.01-3.12 (m, 2H); LC/MS: m/z=359.1 [M+H]⁺ (Calc:358.4).

Example 9

2-Amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide (35) wasprepared according to the same procedure described for preparingcompound 28 in Example 7. Compound 35 was obtained as a HCl-salt (whitesolid): ¹H-NMR (400 MHz, CD₃OD) δ: 7.69-7.71 (m, 1H), 7.4-7.44 (m, 3H),7.28-7.33 (m, 3H), 6.95-7.15 (m, 7H), 4.1-4.14 (m, 1H), 3.37-3.42 (m,1H), 3.21-3.24 (m, 1H); LC/MS: m/z=372.5 [M+H]⁺ (Calc: 371.4).

2-Amino-N-(2-hydroxyethyl)-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide(37) was prepared as follows: A mixture of compound 33 (0.1 g) preparedin Example 8, compound 36 (0.2 mL) and MeOH (0.2 mL) was heated undermicrowave at 100° C. for 30 minutes. The reaction mixture was dilutedwith CHCl₃ (15 mL), washed with water (4 mL), concentrated and purifiedby column (CHCl₃/MeOH 10/3) to afford an oil, which was dissolved in 15mL of HCl (0.25N aqueous), then, freeze dried to afford compound 37 as abrown solid (65 mg, 63%): ¹H-NMR (400 MHz, CD₃OD) δ: 7.75 (d, 1H, 7.4Hz), 7.45-7.57 (m, 3H), 7.34-7.49 (m, 3H), 7.09-7.19 (m, 5H), 7.01-7.04(m, 2H), 3.99-4.04 (m, 1H), 3.39-3.44 (m, 2H), 3.27-3.33 (m, 1H),3.15-3.22 (m, 3H); LC/MS: m/z=416.2 [M+H]⁺ (Calc: 415.5).

Example 10

2-Methanesulfonylamino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide(39) was prepared as follows: MeSO₂Cl (0.3 g, 2.6 mmol) was added to asolution of compound 33 (0.2 g, 0.5 mmol) prepared in Example 8 andtriethylamine (0.5 mL) in CHCl₃ (15 mL) at 0° C. The resulting mixturewas shaken at 30° C. for 48 hours, and then washed with water (4 mL).The solvent was removed to give crude compound 38 (LC/MS: m/z=479.2[M+H]⁺ (Calc: 478.2)), which was dissolved in NH₃ (2 mL 28% aqueous and4 mL 7N in MeOH), and heated to 120° C. for 2 hours under microwave. Thereaction mixture was diluted with CHCl₃ (45 mL), washed with water (10mL), concentrated and purified by column (Silica gel, TCM/MeOH 10/1) togive compound 39 as a brown solid (60 mg, 30% in two steps): ¹H-NMR (400MHz, CDCl₃) δ: 7.61-7.63 (m, 1H), 7.41-7.42 (m, 1H), 7.3-7.34 (m, 4H),7.0-7.18 (m, 8H), 6.13 (br, 1H, NH), 5.57 (br, 1H, NH), 5.2 (d, 1H, 7.9Hz), 4.19-4.25 (m, 1H), 3.32-3.37 (m, 1H), 3.19-3.25 (m, 1H), 2.54 (s,3H); LC/MS: m/z=450.1 [M+H]⁺ (Calc: 449.5).

Example 11

(a) The starting compound5-(4-bromophenoxy)-2-(trifluoromethyl)benzonitrile (30b) was prepared asshown below:

Accordingly, a mixture of compound 40 (1.0 eq, Aldrich), compound 41 (2g, 0.9 eq, Matrix Scientific) and K₂CO₃ (2 eq) in 25 mL of CH₃CN washeated at 80° C. under argon for 14 hours. After cooling to roomtemperature, water (30 mL) was added, extracted with EtOAc (2×100 mL),concentrated and purified by column (silica gel, Hexanes, thenHexanes/EtOAc 10/1) to give compound 30b as a white solid (2.8 g, 81%).¹H-NMR (400 MHz, CDCl₃) δ: 7.75 (d, 1H, 8.8 Hz), 7.57-7.61 (m, 2H),7.36-7.37 (m, 1H), 6.97-7.01 (m, 2H), 7.08-7.11 (m, 2H).

(b) Compounds 43-47 were prepared as follows:

Accordingly, a corresponding mixture of 40a-e (1 mmol, 1.0 eq), compound30a or 30b (1.2 eq), CuI (0.5 eq), K₂CO₃ (3 eq), and dimethylglycine(Aldrich, 0.1 eq) in DMF (10 mL) was heated at 150° C. for 1 hour undermicrowave. The mixture was filtered, and dissolved in water/EtOAc (20mL/100 mL). The organic layer was washed with brine, concentrated andpurified by column (silica gel, CHCl₃, then, CHCl₃/MeOH 10/1) to affordthe desired compounds:

(c) 2-(1-(4-Phenoxyphenyl)-1H-indol-3-yl)ethanamine (43) was obtained asa sticky oil, which was dissolved in 10 mL HCl (0.2N) at roomtemperature, and then freeze dried to give a white solid (HCl-salt,30%): ¹H-NMR (400 MHz, CD₃OD) δ: 7.67-7.71 (m, 1H), 7.51-7.57 (m, 3H),7.4-7.44 (m, 3H), 7.15-7.24 (m, 5H), 7.08-7.11 (m, 2H), 3.19-3.32 (m,4H); LC/MS: m/z=329.2 [M+H]⁺ (Calc: 328.4).

(d)(R)-5-{4-[3-(2-Amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile(44) was obtained as a white solid (yield 50%): ¹H-NMR (400 MHz, CD₃OD)δ: 7.93 (d, 1H, 8.8 Hz), 7.58-7.74 (m, 5H), 7.46-7.50 (m, 2H), 7.36-7.39(m, 2H), 7.19-7.29 (m, 2H), 3.79-3.83 (m, 1H), 3.54-3.68 (m, 2H),3.07-3.22 (m, 1H); LC/MS: m/z=452.2 [M+H]⁺ (Calc: 451.4).

(e)(S)-4-{[3-(2-(Dimethylamino)ethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one(45) was obtained as a white solid (yield 70%): ¹H-NMR (400 MHz, CD₃OD)δ: 7.35-7.48 (m, 6H), 7.24 (s, 1H), 7.05-7.16 (m, 6H), 4.37-4.43 (m,1H), 4.18-4.23 (m, 2H), 2.95-3.09 (m, 6H), 2.54 (s, 6H); LC/MS:m/z=456.2 [M+H]⁺ (Calc: 455.5).

(f)(S)-5-{4-[3-((2-Oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile(46) was obtained as a white solid (yield 75%): ¹H-NMR (400 MHz, CD₃OD)δ: 7.78 (d, 1H, 8.9 Hz), 7.45-7.59 (m, 5H), 7.32-7.35 (m, 1H), 7.28 (s,1H), 7.07-7.24 (m, 4H), 4.35-4.4 (m, 1H), 4.12-4.23 (m, 2H), 2.95-3.09(m, 2H); LC/MS: m/z=478.1 [M+H]⁺ (Calc: 477.4).

(g)(S)-5-{4-[3-(2-Amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile(47): white solid, 40%; ¹H-NMR (400 MHz, CD₃OD) δ: 7.79 (d, 1H, 8.8 Hz),7.46-7.62 (m, 5H), 7.33-7.36 (m, 1H), 7.29 (s, 1H), 7.08-7.24 (m, 4H),3.66 (dd, 1H, 3.9 & 11.2 Hz), 3.51 (dd, 1H, 6.5 & 11.2 Hz), 3.32-3.38(m, 1H), 3.04 (dd, 1H, 6.5 & 14.2 Hz), 2.9 (dd, 1H, 7.0 & 14.2 Hz);LC/MS: m/z=452.2 [M+H]⁺ (Calc: 451.4).

Example 12

(S)-2-Amino-3-[3-(2-(dimethylamino)ethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol(48) was prepared as follows: A mixture of compound 45 prepared inExample 11 (0.2 g, 0.4 mmol), 4 mL NaOH (2N aqueous) and 4 mL of ethanolwas shaken at 80° C. for 2 hours. After cooling to room temperature, thereaction mixture was extracted with CHCl₃, concentrated and purified bycolumn (silica gel, EtOAc/MeOH/NH₄OH 80/20/2) to give compound 48 as asticky oil, which was dissolved in 10 mL of HCl (0.2N aqueous), andfreeze dried to afford a white solid (110 mg, HCl-salt, ˜50%): ¹H-NMR(400 MHz, CD₃OD) δ: 7.72 (s, 1H), 7.49-7.54 (m, 4H), 7.4-7.44 (m, 2H),7.16-7.22 (m, 4H), 7.07-7.11 (m, 2), 3.73-3.75 (m, 1H), 3.53-3.62 (m,4H), 3.08-3.12 (m, 2H), 3.1 (s, 6H); LC/MS: m/z=430.1 [M+H]⁺ (Calc:429.5).

Example 13

(a)5-{4-[3-(1,2-Dihydroxyethyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile(51) was prepared as follows: Compound 49 was prepared according thesame procedure described in Example 8 for preparing compound 31. Oxalylchloride (2M in DCM, Aldrich, 3.0 eq) was added to a solution ofcompound 49 (0.2 g, 1.0 eq) in Et₂O (6 mL) at 0° C. The reaction mixturewas warmed to room temperature over 1 hour. After 1.5 hours at roomtemperature, the reaction mixture was concentrated under vacuum, theresidue was dissolved in chloroform (10 mL) and cooled to 0° C. EtOH (2mL) was added to the above solution, and warmed to room temperature.After 1 hour, the reaction was quenched with water (6 mL), and extractedwith chloroform (2×10 mL), concentrated and purified by column (silicagel, TCM/MeOH 10/1) to give compound 50 as a yellow solid (0.18 g, 72%):¹H-NMR (400 MHz, CDCl₃) δ: 8.48 (s, 1H), 8.42-8.45 (m, 1H), 7.71 (d, 1H,8.8 Hz), 7.54-7.57 (m, 2H), 7.27-7.42 (m, 5H), 7.2-7.23 (m, 2H), 4.35(q, 2H, 7.0 Hz), 1.36 (t, 3H, 7.0 Hz).

(b) A mixture of compound 50 (0.15 g) and NaBH₄ (100 mg) in 10 mL ofEtOH/THF (1/1) was shaken at room temperature for 2 hours. The reactionwas quenched with water, extracted with TCM and purified by column(MeOH/TCM 0.5/10, Rf 0.5) to give the title compound 51 as a white solid(90 mg, 70%): ¹H-NMR (400 MHz, CD₃OD) δ: 7.83 (d, 1H, 8.9 Hz), 7.76-7.78(m, 1H), 7.6-7.63 (m, 2H), 7.57 (s, 1H), 7.54-7.56 (m, 1H), 7.49-7.5 (m,1H), 7.39-7.42 (m, 1H), 7.15-7.3 (m, 4H), 4.68-4.71 (m, 1H), 3.97-4.02(m, 1H), 3.8-3.84 (m, 1H); LC/MS: m/z=461.0 [M+Na⁺] (Calc: 438.4).

Example 14

(a)(S)-5-{4-[3-(2,3-Dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile(54) was prepared as follows: Compound 29 (1.2 g, 1.0 eq) in THF (10 mL)was added to a solution of MeMgBr (3.0N in diethyl ether, Aldrich, 1.2eq) at room temperature. After 1 hour at room temperature, the mixturewas cooled to −10° C., and a solution of allylbromide (Aldrich, 1.0 eq,in 4 mL THF) was added over 5 minutes. The reaction mixture was warmedto room temperature, and left at room temperature for 24 hours. Thereaction was quenched with water (20 mL), extracted with EtOAc (2×100mL), concentrated and purified by column to afford compound 52 as abrown oil (0.8 g, 50%): ¹H-NMR (400 MHz, CDCl₃) δ: 7.9 (br, 1H),7.66-7.68 (m, 1H), 7.37-7.40 (m, 1H), 7.2-7.3 (m, 2H), 7.0-7.02 (m, 1H),6.61-6.63 (m, 1H), 6.1-6.2 (m, 1H), 5.2-5.26 (m, 1H), 5.13-5.16 (m, 1H),3.59-3.61 (m, 2H).

(b) Compound 53 was prepared according the same procedure described inExample 8 for preparing compound 31 using compounds 52 and 30b asstarting materials. Compound 53 was obtained as a yellow oil (60%):LC/MS: m/z=419.1 [M+H⁺] (Calc: 418.4)].

(c) Admix-β (0.2 g, Aldrich) was added to a solution of compound 53 (0.1g) in 30 mL of t-BuOH/water (1/1) at 0° C. The reaction mixture wasslowly warmed to 38° C. for two days. The reaction mixture was dilutedwith water (40 mL), extracted with CHCl₃, concentrated and purified bycolumn (silica gel, TCM/MeOH 10/0.4) to obtain the title compound 54 asa brown solid (50 mg, yield 60%): ¹H-NMR (400 MHz, CD₃OD/CDCl₃ 1/1) δ:7.82 (d, 1H, 8.9 Hz), 7.6-7.7 (m, 3H), 7.5-7.56 (m, 2H), 7.38-7.41 (m,1H), 7.32 (s, 1H), 7.14-7.28 (m, 4H), 4.01-4.05 (m, 1H), 3.5-3.60 (m,2H), 2.9-3.1 (m, 2H); LC/MS: m/z=453.3 [M+H]⁺ (Calc: 452.4).

Example 15

(a) Intermediate 56 was prepared according the same procedure describedin Example 11 for preparing compound 30b using compounds 55 (ALDRICH)and 40 as starting materials. Compound 56 was obtained as a white solid(80%): LC/MS: m/z=275.9 [M+H+] (Calc: 274.1)].

(b)(S)-5-{4-[3-(2-Amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-benzonitrile(57) was prepared according the same procedure described in Example 11for preparing compound 47 using compounds 56 and 40e as startingmaterials. Compound 57 was obtained as a yellow solid (60%): ¹H-NMR (400MHz, CD₃OD): δ 7.6-7.6 (m, 3H), 7.52 (d, 2H, 8.8 Hz), 7.46 (d, 1H, 8.1Hz), 7.35 (s, 1H), 7.08-7.24 (m, 6H), 3.66 (dd, 1H, 3.5 & 11.2 Hz),3.5-3.58 (m, 2H), 3.04-3.14 (m, 2H); LC/MS: m/z=384.1 [M+H]⁺ (Calc:383.4).

Example 16

(a) A mixture of compound 29 (0.5 g, 1.0 eq), compound 30b (1.1 eq), CuI(0.4 eq), K₂CO₃ (3 eq), and N,N-dimethylglycine (0.2 eq) in DMF (10 mL)was heated at 165° C. for 2 hours under microwave. The mixture waspoured into water/EtOAc (40 mL/200 mL). The organic layer was separated,washed with brine, concentrated and purified by column (silica gel,CHCl₃/hexane 1/8) to afford compound 49 as a brown solid (0.82 g, 50%):LC/MS: m/z=379.2 [M+H]⁺ (Calc: 378.4).

(b) Compound 58 (2N in DCM, 1 mL) was added to a solution of compound 49(0.5 g) in 10 mL of Et₂O at 0° C. The reaction mixture was shaken at 0°C. for 1.5 hours and then concentrated under vacuum. The residue wasquenched with ammonium hydroxide (29% aqueous) at 0° C., shaken at roomtemperature for 1 hour, extracted with EtOAc, and purified by column(CHCl₃/MeOH 10/1) to give compound 59 as a white solid (0.15 g, 26%):¹H-NMR (400 MHz, CDCl₃): δ 9.05 (s, 1H), 8.43-8.46 (m, 1H), 7.73 (d, 1H,8.9 Hz), 7.56 (d, 2H, 8.9 Hz), 7.4-7.45 (m, 2H), 7.26-7.36 (m, 4H), 7.22(d, 2H, 8.9 Hz), 5.47 (br, 1H), 3.79 (d, 2H, 5.8 Hz); LC/MS: m/z=450.1[M+H]⁺ (Calc: 449.4).

(c) NaBH₄ (40 mg) was added to a solution of compound 59 in EtOH/THF (2mL/2 mL) at room temperature, and the mixture was shaken at roomtemperature for 3 hours. The reaction was quenched with water, extractedwith EtOAc (30 mL), concentrated, and purified by column (CHCl₃/MeOH7/1) to give compound 60 as a white solid (70 mg, 70%): ¹H-NMR (400 MHz,CD₃OD): δ7.92 (d, 1H, 8.8 Hz), 7.87 (d, 1H, 7.9 Hz), 7.66-7.69 (m, 3H),7.53-7.56 (m, 2H), 7.45-7.48 (m, 1H), 7.35-7.38 (m, 1H), 7.15-7.25 (m,2H), 5.41 (br, 1H); LC/MS: m/z=474.3 [M+Na]⁺ (Calc: 451.4).

Example 17

The title compound 65 (white solid) was prepared following the sameprocedure used for preparing compound 60 in Example 16: ¹H-NMR (400 MHz,CD₃OD): δ8.24 (s, 1H), 7.92 (dd, 1H, 1.5 & 8.5 Hz), 7.8-7.84 (m, 2H),7.62 (s, 1H), 7.59 (d, 2H, 8.9 Hz), 7.48 (d, 1H, 2.6 Hz), 7.37-7.39 (m,1H), 7.28-7.3 (m, 1H), 6.35 (br, 1H), 5.7 (br, 1H), 5.51 (s, 1H), 3.95(s, 3H); LC/MS: m/z=532.0 [M+Na]⁺ (Calc: 509.4).

Example 18

(a) Compound 58 (2N in DCM, 1 mL) was added to a solution of 49 (0.5 g)in 10 mL of Et₂O at 0° C. The reaction mixture was shaken at 0° C. for1.5 hours and then concentrated under vacuum. The residue was dissolvedin DCM (4 mL) and treated with compound 66 (1.5 eq) at 0° C. The mixturewas shaken at room temperature for 30 min and then concentrated, andpurified by column (CHCl₃/MeOH 10/1) to give compound 67 as a sticky oil(LC/MS: m/z=490.0 [M+H]⁺ (Calc: 489.4), which was suspended in 20 mL oftert-BuOH/water (1/1) and cooled to 0° C. Ad-mix-α (1.5 g) was added tothe reaction mixture, and the resulting mixture was shaken at roomtemperature for 36 hours. Water (15 mL) and EtOAc (40 mL) were added tothe reaction mixture. The organic layer was separated, washed withbrine, concentrated and purified by column (silica gel, EtOAc/MeOH 10/1)to give compound 68 as a white solid (0.2 g, 29% in two steps): ¹H-NMR(400 MHz, CD₃OD): δ 9.02 (s, 1H), 8.43-8.46 (m, 1H), 7.9 (d, 1H, 8.9Hz), 7.72 (d, 2H, 8.8 Hz), 7.62 (d, 1H, 2.6 Hz), 7.53-7.56 (m, 1H),7.45-7.48 (m, 1H), 7.35-7.4 (m, 4H), 3.82-3.86 (m, 1H), 3.55-3.61 (m,3H), 3.38-3.42 (m, 1H); LC/MS: m/z=524.0 [M+H]⁺ (Calc: 523.4).

(b) NaBH₄ (20 mg) was added to a solution of compound 68 (50 mg) inEtOH/THF (2 mL/2 mL) at room temperature, and the mixture was shaken atroom temperature for 1 hour. The reaction was quenched with water,extracted with EtOAc (30 mL), concentrated, and purified by column(CHCl₃/MeOH 10/1.5) to give compound 69 as a white solid (40 mg, 40%):¹H-NMR (400 MHz, CD₃OD): δ 7.72-7.76 (m, 2H), 7.49-7.53 (m, 2H),7.3-7.46 (m, 4H), 7.05-7.21 (m, 4H), 5.35-5.37 (m, 1H), 3.67-3.73 (m,1H), 3.43-3.47 (m, 3H), 3.28-3.32 (m, 1H); LC/MS: m/z=548.2 [M+Na]⁺(Calc: 525.4).

Example 19

(a) Compound 71 (white solid, 70%) was prepared following the proceduredescribed in Example 1 for preparing compound 3: ¹H-NMR (400 MHz,CD₃OD): δ 8.12 (br, 1H), 7.75 (s, 1H), 7.52 (d, 2H, 8.9 Hz), 7.32-7.44(m, 3H), 7.15-7.17 (i, 1H), 6.94-6.98 (i, 5H), 6.52-6.54 (i, 1H).

(b) Sodium bis(trimethylsilyl)amide (2 mL, 1.0 M in THF, Aldrich) wasadded to a solution of compound 71 (0.2 g) and compound 72 (0.25 mL) in10 mL of THF at room temperature. The reaction mixture was shaken atroom temperature for 36 hours. The reaction was quenched with water (20mL), extracted with EtOAc, concentrated and purified by column (silicagel, EtOAc/hexanes 10/1) to get a crude compound 73 (80 mg, 30%, (LC/MS:m/z=384.2 [M+H]⁺ (Calc: 383.4).

(c) Ad-mix-α (0.8 g) was added to a solution of compound 73 (50 mg) in10 mL of t-BuOH/water (1/1) at room temperature. The mixture was shakenat room temperature for 36 hours. Water (15 mL) and EtOAc (40 mL) wereadded to the reaction mixture. The organic layer was separated, washedwith brine, concentrated and purified by column (silica gel, CHCl₃/MeOH10/1) to give the title compound 74 as a white solid (40 mg, 50%):¹H-NMR (400 MHz, CD₃OD): δ 7.81 (d, 1H, 1.3 Hz), 7.65 (d, 2H, 8.6 Hz),7.4-7.5 (m, 2H), 7.02-7.16 (m, 7H), 4.3-4.36 (m, 1H), 4.09-4.16 (m, 1H),3.96-4.02 (m, 2H), 3.52-3.62 (m, 4H), 3.0-3.06 (m, 1H), 2.84-2.91 (m,1H); LC/MS: m/z=452.2 [M+H]⁺ (Calc: 451.5).

Example 20

(a) Compound 29 (5 g, 42 mmol in 10 mL THF) was added to a solution ofethylmagnesium bromide (1.0 M in THF, 50 mL, Aldrich) at roomtemperature under argon. The resulting mixture was stirred at roomtemperature for 2 hours. The reaction mixture was cooled to −20° C., anda solution of compound 72 (6 g, in 20 mL of THF) was added to the cooledreaction mixture over 5 min. The reaction mixture was allowed to warm toroom temperature over night. The reaction was quenched with water (40mL), and extracted with EtOAc (2×200 mL). The combined organic layer waswashed with brine, concentrated and purified by column to get compound52 as a colorless oil (4 g, 60%): ¹H-NMR (400 MHz, CDCl₃): δ 7.87 (br,1H, NH), 7.67 (dd, 1H, 1.0 & 7.9 Hz), 7.37-7.4 (m, 1H), 7.25 (dt, 1H,1.3 & 8.1 Hz), 7.16-7.19 (m, 1H), 7.0-7.1 (m, 1H), 6.08-6.18 (m, 1H),5.2-5.26 (m, 1H), 5.11-5.15 (m, 1H), 3.57-3.59 (m, 2H).

(b) A mixture of compound 52 (0.3 g, 1.0 eq), compound 56 (1.1 eq), CuI(0.2 eq), K₂CO₃ (3 eq), and N,N-dimethylglycine (0.1 eq) in DMF (10 mL)was heated at 165° C. for 2 hours under microwave. The mixture waspoured into water/EtOAc (40 mL/200 mL). The organic layer was washedwith brine, concentrated and purified by column (silica gel,CHCl₃/hexane 2/7) to afford compound 75 as a colorless oil (0.42 g,58%): ¹H-NMR (400 MHz, CDCl₃): δ 7.56-7.61 (m, 3H), 7.45-7.48 (m, 3H),7.11-7.18 (m, 4H), 7.06-7.07 (m, 1H), 7.0-7.03 (m 2H), 5.12-5.19 (m,1H), 5.03-5.07 (m, 1H), 3.5-3.53 (m, 2H).

(c) Ad-mix-α (1.5 g) was added to a solution of compound 75 (0.2 g) in30 mL of t-BuOH/water (1/1) at 0° C. The mixture was shaken at roomtemperature for 36 hours. Water (40 mL) and EtOAc (100 mL) were added tothe reaction mixture. The organic layer was separated, washed withbrine, concentrated and purified by column (silica gel, CHCl₃/MeOH 10/1)to give the title compound 76 as a yellow solid (160 mg, 72%): ¹H-NMR(400 MHz, CD₃OD): δ 7.74-7.78 (m, 2H), 7.68-7.71 (m, 1H), 7.61-7.64 (m,2H), 7.53-7.56 (m, 1H), 7.36 (s, 1H), 7.28-7.31 (m, 2H), 7.13-7.23 (m,4H), 3.98-4.04 (m, 1H), 3.55-3.64 (m, 2H), 3.05-3.09 (m, 1H), 2.88-2.94(m, 1H); LC/MS: m/z=385.1 [M+H]⁺ (Calc: 384.4).

(d) Ad-mix-β (1.5 g) was added to a solution of compound 75 (0.2 g) in30 mL of t-BuOH/water (1/1) at 0° C. The mixture was shaken at roomtemperature for 36 hours. Water (40 mL) and EtOAc (100 mL) were added tothe reaction mixture. The organic layer was separated, washed withbrine, concentrated and purified by column (silica gel, CHCl₃/MeOH 10/1)to give the title compound 77 as a yellow solid (180 mg, 80%): ¹H-NMR(400 MHz, CD₃OD): δ 7.74-7.78 (m, 2H), 7.68-7.71 (m, 1H), 7.61-7.64 (m,2H), 7.53-7.56 (m, 1H), 7.36-7.38 (m, 1H), 7.28-7.31 (m, 2H), 7.13-7.23(m, 4H), 3.98-4.04 (m, 1H), 3.55-3.64 (m, 2H), 3.05-3.09 (m, 1H),2.88-2.93 (m, 1H); LC/MS: m/z=385.1 [M+H]⁺ (Calc: 384.4).

Example 21

(a) Compound 80 (white solid) was prepared according to the proceduredescribed for preparing compound 76 in Example 20, wherein compound 52is reacted with compound 78 (1-trifluoromethyl-4-(4-iodophenoxy)benzeneprepared in Example 33): ¹H-NMR (400 MHz, CD₃OD): δ7.57-7.61 (m, 3H),7.51 (d, 1H, 8.8 Hz), 7.42-7.45 (m, 1H), 7.25 (s, 1H), 7.17 9d, 2H, 8.9Hz), 7.04-7.14 (m, 4H), 3.88-3.94 (m, 1H), 3.45-3.56 (m, 2H), 2.93-2.95(m, 1H), 2.77-2.84 (m, 1H); LC/MS: m/z=450.2 [M+Na]⁺ (Calc: 427.4).

(b) Compound 83 (yellow solid) was prepared according to the proceduredescribed for preparing compound 76 in Example 20, wherein compound 52is reacted compound 81 (4-bromophenoxy-5-trifluoromethylpyridineprepared in Example 35): ¹H-NMR (400 MHz, CD₃OD): δ 8.36 (s, 1H), 7.98(dd, 1H, 2.6 & 8.8 Hz), 7.58 (d, 1H, 7.8 Hz), 7.45-7.52 (m, 3H),7.22-7.26 (m, 3H), 7.04-7.14 (m, 3H), 3.9-3.95 (m, 1H), 3.45-3.56 (m,2H), 2.93-2.99 (m, 1H), 2.8-2.84 (m, 1H); LC/MS: m/z=429.1 [M+H]⁺ (Calc:428.4).

Example 22

(a) General procedure for the synthesis of intermediates 86 and 88:Compound 84 (1.05 eq) was added to a solution of the amine 85 or 87 (1.0eq) and pyridine (1.2 eq) in 10 mL of THF at 0° C. The reaction mixturewas allowed to warm to room temperature over 1 hour, and the mixture wasshaken at room temperature for 2 hours. The reaction mixture wasquenched with water (20 mL), and extracted with EtOAc (40 mL). Theorganic layer was separated and washed with HCl (0.4N, 10 mL) and brine,and concentrated to give the desired compound 86 and 88, respectively,as a pink solid (˜90%).

Compound 86: ¹H-NMR (400 MHz, CDCl₃) δ 7.58-7.64 (m, 4H), 7.04-7.08 (m,2H), 6.96-7.01 (m, 2H), 6.69 (br, 1H).

Compound 88: ¹H-NMR (400 MHz, CDCl₃) δ 7.63 (d, 2H, 8.8 Hz), 7.42 (d,2H, 8.8 Hz), 7.0-7.09 (m, 4H), 3.18 (s, 3H).

(b) The title compound 90 (white solid) was prepared following theprocedure described for preparing compound 76 in Example 20: ¹H-NMR (400MHz, CD₃OD): δ 7.45-7.56 (m, 6H), 7.26 (s, 1H), 6.96-7.08 (m, 4H),6.88-6.92 (m, 2H), 3.76-3.82 (m, 1H), 3.32-3.42 (m, 2H), 3.03 (s, 3H),2.82-2.88 (m, 1H), 2.64-2.72 (m, 1H); LC/MS: m/z=455.2 [M+H]⁺ (Calc:454.5).

(c) The title compound 92 (white solid) was prepared following theprocedure described for preparing compound 76 in Example 20: ¹H-NMR (400MHz, CD₃OD): δ 7.78 (d, 2H, 8.9 Hz), 7.57-7.61 (m, 3H), 7.49-7.52 (m,1H), 7.3 (s, 1H), 7.03-7.15 (m, 4H), 6.88-6.92 (m, 2H), 3.84-3.92 (m,1H), 3.41-3.52 (m, 2H), 2.91-2.98 (m, 1H), 2.74-2.79 (m, 1H); LC/MS:m/z=441.1 [M+H]⁺ (Calc: 440.5).

Example 23

(a) n-BuLi (15 mL, 2.5 M in hexanes, Aldrich) was added to a suspensionof compound 94 (15 g) in 100 mL of THF at −40° C. The reaction mixturewas warmed to 0° C. over a period of 2 hours and then cooled to −30° C.In another flask, sodium bis(trimethylsilyl)amide (34 mL, 1M in THF) wasadded to a solution of compound 93 (5 g) in 40 mL THF at roomtemperature. The resulting solution was transferred to the above cooledsolution (−30° C.). The resulting suspension was allowed to warm to roomtemperature over night. The reaction was quenched with water (100 mL),extracted with EtOAc (2×200 mL), washed with brine, concentrated andpurified by column (EtAOc/hexanes 2/9) to obtain compound 95 as acolorless oil (4 g, 80%).

(b) A mixture of compound 95 (0.3 g, 1.0 eq), compound 30b (1.1 eq), CuI(0.2 eq), K₂CO₃ (3 eq), and N,N-dimethylglycine (0.1 eq) in DMF (10 mL)was heated at 165° C. for 2 hours under microwave. The mixture waspoured into water/EtOAc (40 mL/200 mL). The organic layer was washedwith brine, concentrated and purified by column (silica gel,CHCl₃/hexane 2/7) to afford compound 96 as a white solid (0.42 g, 48%):¹H-NMR (400 MHz, CDCl₃): δ 7.79 (d, 1H, 8.7 Hz), 7.72 (s, 1H), 7.2-7.61(m, 9H), 6.84 (dd, 1H, 10.9 & 17.5 Hz), 6.72 (d, 1H, 3.3 Hz), 5.76 (d,1H, 17.5 Hz), 5.22 (d, 1H, 10.9 Hz).

(c) Compound 58 (2N in DCM, 0.4 mL) was added to a solution of compound96 (0.2 g) in 10 mL of Et₂O at 0° C. The reaction mixture was shaken at0° C. for 1.5 hours and then concentrated under vacuum. The residue wasdissolved in DCM/MeOH (4 mL/2 mL) at 0° C. The mixture was shaken atroom temperature for 30 min, and then concentrated and purified bycolumn (CHCl₃/MeOH 10/0.2) to give compound 97 as a sticky oil (0.1 g,42%, LC/MS: m/z=491.2 [M+H]⁺ (Calc: 490.4)).

(d) Ad-mix-β (1.0 g) was added to a suspension of compound 97 (0.1 g) in20 mL of t-BuOH/water (1/1) at 0° C. The reaction mixture was shaken atroom temperature for 36 hours. Water (15 mL) and EtOAc (40 mL) wereadded to the reaction mixture. The organic layer was separated,neutralized to pH˜4, washed with brine, concentrated and purified bycolumn (silica gel, EtOAc/MeOH 5/2) to give the title compound 98 as ayellow solid (30 mg): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.52 (s, 1H), 8.24(s, 1H), 7.96 (d, 1H, 8.8 Hz), 7.91 (d, 1H, 2.6 Hz), 7.74 (d, 2H, 8.8Hz), 7.3-7.5 (m, 5H), 4.63 (t, 1H, 6.1 Hz), 3.38-3.42 (m, 4H); LC/MS:m/z=511.1 [M+H]⁺ (Calc: 510.4).

Example 24

(a) A mixture of compound 99 (0.5 g, 1.0 eq), compound 100 (1.1 eq), CuI(0.4 eq), K₂CO₃ (3 eq), and N,N-dimethylglycine (0.2 eq) in DMF (10 mL)was heated at 165° C. for 2 hours under microwave. The mixture waspoured into water/EtOAc (40 mL/200 mL). The organic layer was washedwith brine, concentrated and purified by column (silica gel,EtOAc/hexane 1/7) to afford compound 101 as a colorless oil (0.8 g,70%): ¹H-NMR (400 MHz, CDCl₃): δ 7.71 (s, 1H), 7.66 (dd, 1H, 0.66 & 8.1Hz), 7.41 (d, 1H, 3.3 Hz), 7.3-7.34 (m, 3H), 6.99-7.07 (m, 6H), 6.67(dd, 1H, 0.88 & 3.28 Hz).

(b) NBS (0.2 g) was added to a solution of compound 101 (0.3 g) in 10 mLof DCM at 0° C. After 2 hours at 0-5° C., the reaction was quenched withaqueous NaOH (0.2N 10 mL), and extracted with DCM (2×30 mL). Thecombined organic layer was washed with brine and concentrated to givecompound 102 as a yellow solid: ¹H-NMR (400 MHz, CDCl₃): δ 7.66 (s, 1H),7.63 (d, 1H, 8.3 Hz), 7.44 (s, 1H), 7.4 (dd, 1H, 0.87 & 8.3 Hz), 7.31(d, 2H, 8.3 Hz), 7.01-7.07 (m, 6H).

(c) To a solution of compound 102 (0.3 g, 1.0 eq) in 1,4-dioxane (10 mL)was added compound 103 (1.5 eq), CsF (3.0 eq) and PdCl₂(dppf).CH₂Cl₂(0.2 eq) at room temperature under N₂. The mixture was shaken at 90° C.for 2 hours. The reaction mixture was diluted with H₂O (20 mL) and thenextracted with EtOAc (2×40 mL). The organic layer were washed withbrine, evaporated and purified by column (silica gel, EtOAc/Hexanes5/95) to get compound 104 as a colorless oil (0.15 g, 55%, LC/MS:m/z=369.2 [M+H]⁺ (Calc: 368.4)).

(d) Ad-mix-α (1.0 g) was added to a solution of compound 104 (0.15 g) in30 mL of i-PrOH/water (2/1) at room temperature. The reaction mixturewas shaken at room temperature for 36 hours. Water (40 mL) and EtOAc(100 mL) were added to the reaction mixture. The organic layer wasseparated, washed with brine, concentrated and purified by column(silica gel, CHCl₃/MeOH 10/1) to give the title compound 105 as a whitesolid (100 mg, 60%): ¹H-NMR (400 MHz, CD₃OD): δ 7.75 (dd, 1H, 0.6 & 8.3Hz), 7.7-7.71 (m, 1H), 7.49 (s, 1H), 7.41-7.45 (m, 2H), 7.30 (dd, 1H,1.3 & 8.1 Hz), 7.01-7.07 (m, 6H), 3.82-3.88 (m, 1H), 3.42-3.5 (m, 2H),2.96-3.02 (m, 1H), 2.76-2.82 (m, 1H); LC/MS: m/z=403.2 [M+H]⁺ (Calc:402.4).

Example 25

Compound 110 (white solid) was prepared following the proceduredescribed for preparing compound 105 in Example 24: ¹H-NMR (400 MHz,CD₃OD): δ 8.05-8.06 (m, 1H), 7.35-7.47 (m, 5H), 7.69-7.07 (m, 6H),3.81-3.87 (m, 1H), 3.44-3.5 (m, 2H), 2.96-3.02 (m, 1H), 2.76-2.82 (m,1H); LC/MS: m/z=403.1 [M+H]⁺ (Calc: 402.4).

Example 26

Compound 115 (white solid) was prepared following the proceduredescribed for preparing compound 105 in Example 24: ¹H-NMR (400 MHz,CD₃OD/CDCl₃ 1/1): 6 8.01 (d, 1H, 1.1 & 7.9 Hz), 7.54 (dd, 1H, 1.1 & 7.6Hz), 7.44 (d, 2H, 8.9 Hz), 7.29 (s, 1H), 7.23 (dd, 1H, 7.6 & 7.8 Hz),7.05-7.17 (m, 6H), 3.93-3.97 (m, 1H), 3.53-3.62 (m, 2H), 2.05-3.1 (m,1H), 2.87-2.93 (m, 1H); LC/MS: m/z=403.1 [M+H]⁺ (Calc: 402.4).

Example 27

Compound 120 (white solid) was prepared following the proceduredescribed for preparing compound 105 in Example 24: ¹H-NMR (400 MHz,CD₃OD) δ: 7.95-7.96 (m, 1H), 7.63-7.66 (m, 1H), 7.54-7.57 (m, 1H),7.44-7.47 (m, 2H), 7.39 (s, 1H), 7.01-7.07 (m, 6H), 3.86-3.98 (m, 1H),3.42-3.52 (m, 2H), 2.96-3.02 (m, 1H), 2.76-2.82 (m, 1H); LC/MS:m/z=403.1 [M+H]⁺ (Calc: 402.4).

Example 28

General procedure for the preparation of compounds 122 and 123: To amixture of compound 120 (100 mg, or 105) in EtOH/water (6 mL/2 mL) atroom temperature was added the catalyst 121 (10 mg). The resultingmixture was shaken at 84° C. for 16 hours. The solvent was evaporatedand the residue was purified by column (TCM/MeOH 10/0.5) to get thedesired product as a white solid (˜80%).

Compound 122: ¹H-NMR (400 MHz, CD₃OD) δ 7.47-7.51 (m, 1H), 7.35 (d, 2H,8.9 Hz), 7.27 (s, 1H), 7.23 (dd, 1H, 0.8 & 7.3 Hz), 6.98-7.17 (m, 6H),3.86-3.98 (m, 1H), 3.42-3.52 (m, 2H), 2.96-3.02 (m, 1H), 2.76-2.82 (m,1H); LC/MS: m/z=421.2 [M+H]⁺ (Calc: 420.4).

Compound 123: ¹H-NMR (400 MHz, CD₃OD) δ: 7.95-7.96 (m, 1H), 7.63-7.66(m, 1H), 7.54-7.57 (m, 1H), 7.44-7.47 (m, 2H), 7.39 (s, 1H), 7.01-7.07(m, 6H), 3.82-3.88 (m, 1H), 3.44-3.56 (m, 2H), 3.0-3.05 (m, 1H),2.84-2.92 (m, 1H); LC/MS: m/z=421.2 [M+H]⁺ (Calc: 420.4).

Example 29

(a) Compound 128 (white solid) was prepared following the proceduredescribed for preparing compound 105 in Example 24: ¹H-NMR (400 MHz,CDCl₃): δ 7.6-7.72 (m, 3H), 7.47 (d, 2H, 8.9 Hz), 7.35 (d, 1H, 2.4 Hz),7.25-7.3 (m, 2H), 7.15-7.21 (m, 4H), 3.93 (s, 3H), 3.86-3.89 (m, 1H),3.67-3.72 (m, 1H), 3.53-3.58 (m, 1H), 3.13-3.19 (m, 1H), 2.99-3.05 (m,1H).

(b) NaOH (1N 0.4 mL) was added to a solution of compound 128 (20 mg in 4mL EtOH), and the reaction mixture was shaken at room temperature for 5hours. The solvent was evaporated and the residue was dissolved in 1 mLof water and 1 mL of CH₃CN, and purified by HPLC to give the titlecompound 129 as a white solid (15 mg, 80%): ¹H-NMR (400 MHz, CD₃OD): δ7.84 (s, 1H, 8.9 Hz), 7.54-7.64 (m, 5H), 7.41 (s, 1H), 7.35-7.38 (m,1H), 7.27 (d, 2H, 8.9 Hz), 7.14 (dd, 1H, 7.5 & 8.3 Hz), 3.78-3.84 (m,1H), 3.51-3.55 (m, 1H), 3.38-3.44 (m, 1H), 3.15-3.18 (m, 1H), 2.86-2.92(m, 1H); LC/MS: m/z=497.0 [M+H]⁺ (Calc: 496.4).

Example 30

(a) Compound 132 (white solid) was prepared following the proceduredescribed for preparing compound 96 in Example 23: ¹H-NMR (400 MHz,CDCl₃): δ 7.69 (d, 1H, 8.9 Hz), 7.51 (d, 2H, 8.6 Hz), 7.36-7.42 (m, 2H),7.31 (d, 1H, 3.5 Hz), 7.25-7.28 (m, 2H), 7.14-7.16 (m, 2H), 7.05-7.11(m, 1H), 6.84 (dd, 1H, 0.8 & 3.5 Hz), 5.87 (dd, 1H, 1.1 & 17.5 Hz), 5.36(dd, 1H, 1.1 & 10.9 Hz).

(b) AD-Mix-α (1.6 g) was added to a mixture of compound 132 (0.3 g) inwater/i-PrOH (4 mL/8 mL), and the mixture was shaken at room temperaturefor 16 hours. The reaction was quenched with water, extracted withEtOAc, and purified by column (Silica gel, EtOAc, Rf 0.5) to givecompound 133 as a white solid (0.2 g): ¹H-NMR (400 MHz, CDCl₃): δ 7.69(d, 1H, 8.9 Hz), 7.51 (d, 2H, 8.6 Hz), 7.41-7.45 (m, 1H), 7.36 (d, 1H,2.2 Hz), 7.31 (d, 1H, 3.3 Hz), 7.26-7.29 (m, 1H), 7.15-7.12 (m, 4H),6.78 (dd, 1H, 0.8 & 3.5 Hz), 5.24 (dd, 1H, 4.3 & 7.5 Hz), 3.84-3.88 (m,2H).

(c) p-Toluenesulfonic acid (30 mg) was added to a solution of compound133 (0.2 g) and compound 134 (0.4 mL) in 5 mL of DMF at roomtemperature. The reaction mixture was shaken at room temperature for 4hours. The reaction mixture was diluted with water (20 mL), andextracted with EtOAc (100 mL). The organic layer was washed with brine,concentrated and purified by column to give compound 135 as a colorlessoil (silica gel, EtOAc/Hexanes 3/8 Rf 0.6; LC/MS: m/z=501.2 [M+Na]⁺(Calc: 478.5).

(d) NBS (0.1 g) was added to a solution of compound 135 (0.25 g) in 8 mLof DCM at 0° C. After 30 min at 0° C., the reaction was diluted withwater (4 mL) and DCM (30 mL), and then neutralized with NaHCO₃ to pH ˜7.The organic layer was washed with brine and concentrated to get crudecompound 136 as a white solid (0.28 g, 90%; LC/MS: m/z=580.0 [M+Na]⁺(Calc: 557.4).

(e) To a solution of the crude compound 136 (0.25 g, 1.0 eq) in1,4-dioxane (10 ml) was added compound 103 (1.5 eq), CsF (3.0 eq) andPdCl₂(dppf).CH₂Cl₂ (0.2 eq) at room temperature under N₂. The mixturewas shaken at 90° C. for 16 hours. The reaction mixture was diluted withH₂O (20 mL), and then extracted with EtOAc (2×40 mL). The organic layerwas washed with brine, evaporated and purified by column (silica gel,EtOAc/Hexanes 1/9) to get compound 137 as a yellow oil (0.12 g, 50%,LC/MS: m/z=519.2 [M+H]⁺ (Calc: 518.5).

(f) Ad-mix-β (1.0 g) was added to a solution of compound 137 (0.12 g) in15 mL of i-PrOH/water (2/1) at room temperature. The reaction mixturewas shaken at room temperature for 36 hours. Water (40 mL) and EtOAc(100 mL) were added to the reaction mixture. The organic layer wasseparated, washed with brine, concentrated and purified by column(silica gel, CHCl₃/MeOH 10/1) to give compound 138 as a white solid (70mg, 70%; LC/MS: m/z=575.2 [M+Na]⁺ (Calc: 552.5)).

(g) 0.5N HCl (3 mL aqueous) was added to a solution of compound 138 (50mg) in 4 mL THF at room temperature. The reaction mixture was shaken atroom temperature for 24 hours, the solvent was removed and the mixturewas purified by HPLC to get the title compound 139 as a diastereomericmixture (white solid, 40 mg): ¹H-NMR (400 MHz, CD₃OD): δ 7.8 (d, 1H, 8.9Hz), 7.5-7.54 (m, 3H), 7.32-7.37 (m, 2H), 7.29 (s, 1H), 7.21-7.25 (m,3H), 7.08-7.12 (m, 1H), 5.4-5.5 (m, 1H), 3.89-3.93 (m, 1H), 3.7-3.74 (m,1H), 3.45-3.61 (3H), 3.1-3.14 (m, 1H), 2.85-2.91 (m, 1H); LC/MS:m/z=535.2 [M+Na]⁺ (Calc: 512.5).

Example 31

Compound 141 (white solid) was prepared following the proceduredescribed for preparing compound 139 using Ad-mix-α instead of Ad-mix-β:¹H-NMR (400 MHz, CD₃OD): δ 7.82 (d, 1H, 8.8 Hz), 7.53-7.57 (m, 3H),7.34-7.39 (m, 2H), 7.31 (s, 1H), 7.23-7.27 (m, 3H), 7.1-7.14 (m, 1H),5.44-5.51 (m, 1H), 3.89-3.95 (m, 1H), 3.72-3.76 (m, 1H), 3.47-3.63 (m,3H), 3.12-3.18 (m, 1H), 2.86-2.97 (m, 1H); LC/MS: m/z=535.2 [M+Na]⁺(Calc: 512.5).

Example 32

(a) A mixture of compound 142 (Accela ChemBio, 0.5 g, 1.0 eq), compound30a (Aldrich, 1.1 eq), CuI (0.5 eq), K₂CO₃ (3 eq), andN,N-dimethylglycine (Aldrich, 0.1 eq) in DMF (10 mL) was heated at 165°C. for 2 hours under microwave. The mixture was poured into water/EtOAc(40 mL/200 mL). The organic layer was washed with brine, concentratedand purified by column (silica gel, CHCl₃/hexane 1/10) to affordcompound 143 as a brown solid (0.8 g): LC/MS: m/z=359.2 [M+H]⁺ (Calc:358.4).

(b) A mixture of compound 143 (0.15 g) and NH₃ (˜7N in MeOH 5 mL) washeated under microwave at 100° C. for 2 hours. The reaction mixture wasevaporated and purified by column (silica gel, CHCl₃/MeOH 10/0.5) toafford the title compound 145 as a white solid (50 mg, 38%): ¹H-NMR (400MHz, CDCl₃) δ: 8.39 (ddd, 1H, 0.8, 1.0 & 8.1 Hz), 7.58-7.61 (m, 3H),7.39-7.44 (m, 1H), 7.28-7.35 (m, 3H), 7.1-7.15 (m, 3H), 7.02-7.05 (m,2H), 6.94 (br, 1H), 5.51 (br, br, 1H); LC/MS: m/z=330.1 [M+H]⁺ (Calc:329.4).

(c) The title compound 146 (brown solid, 30%) was prepared following theprocedure described for preparing compound 145 above using hydroxylamine(50% solution in water, Aldrich): ¹H-NMR (400 MHz, CDCl₃) δ: 8.32 (d,1H, 8.1 Hz), 7.72-7.77 (m, 3H), 7.5-7.54 (m, 1H), 7.34-7.44 (m, 3H),7.16-7.22 (m, 3H), 7.08-7.12 (m, 2H); LC/MS: m/z=346.1 [M+H]⁺ (Calc:345.4).

(d) The title compound 144 (white solid, 65%) was prepared following theprocedure described for preparing compound 145 using ethanolamine(Aldrich): ¹H-NMR (400 MHz, CDCl₃) δ: 8.33 (d, 1H, 8.1 Hz), 7.74-7.78(m, 3H), 7.49-7.54 (m, 1H), 7.34-7.45 (m, 3H), 7.16-7.22 (m, 3H),7.08-7.12 (m, 2H), 3.78 (t, 2H, 5.7 Hz), 3.61 (t, 2H, 5.8 Hz); LC/MS:m/z=374.2 [M+H]⁺ (Calc: 373.4).

Example 33

(a) H₂SO₄ (1.5 mL) was added to a solution of compound 147 (5 g, AccelaChemBio) in EtOH (150 mL) at room temperature. The reaction mixture washeated at 80° C. under nitrogen for 24 hours. The mixture wasconcentrated to 40 mL, and diluted with EtOAc/water (200 mL/50 mL). Theorganic layer was washed with brine, and concentrated to give compound148 as a white solid (5 g, 86%): ¹H-NMR (400 MHz, CDCl₃) δ: 7.78 (dd,1H, 4.3 & 9.2 Hz), 7.73 (dd, 1H, 1.9 & 8.7 Hz), 7.15-7.21 (m, 1H), 4.5(q, 2H, 7.2 Hz), 1.43 (t, 3H, 7.1 Hz).

(b) The title compound 150 was prepared following the proceduredescribed for preparing compound 145 in Example 32: ¹H-NMR (400 MHz,CD₃OD) δ: 8.96 (dd, 1H, 2.4 & 8.7 Hz), 7.81-7.88 (m, 3H), 7.72 (d, 2H,8.9 Hz), 7.31-7.38 (m, 3H), 7.24 (d, 2H, 8.9 Hz); LC/MS: m/z=416.0[M+H]⁺ (Calc: 415.3).

Example 34

The title compound 152 (white solid) was prepared following theprocedure described for preparing compound 145 in Example 32: ¹H-NMR(400 MHz, CD₃OD) δ: 8.38 (d, 1H, 4.3 Hz), 7.81-7.91 (m, 3H), 7.78 (d,2H, 8.9 Hz), 7.5-7.54 (m, 2H), 7.32-7.42 (m, 4H); LC/MS: m/z=423.1[M+H]⁺ (Calc: 422.4).

Example 35

(a) Compound 81 was prepared following the procedure described forpreparing compound 30b: ¹H-NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 7.94(ddd, 1H, 0.6, 2.6 & 8.6 Hz), 7.56 (d, 2H, 8.9 Hz), 7.05-7.08 (m, 3H).

(b) The title compound 155 (white solid) was prepared following theprocedure described for preparing compound 145 in Example 32: ¹H-NMR(400 MHz, CD₃OD) δ 8.37-8.38 (m, 1H), 8.31 (ddd, 1H, 0.8, 1.0 & 8.3 Hz),7.92-7.95 (m, 1H), 7.74 (d, 2H, 8.9 Hz), 7.69 (d, 1H, 8.6 Hz), 7.41-7.45(m, 1H), 7.29-7.33 (m, 3H); LC/MS: m/z=399.1 [M+H]⁺ (Calc: 398.3).

Example 36

(a) Compound 56 was prepared following the procedure used for preparingcompound 30b: ¹H-NMR (400 MHz, CDCl₃) δ 7.64 (d, 2H, 8.9 Hz), 7.54 (d,2H, 8.8 Hz), 7.03 (d, 2H, 8.9 Hz), 7.67 (d, 2H, 8.9 Hz).

(b) The title compound 159 (white solid) was prepared following theprocedure used for preparing compound 145 in Example 32: ¹H-NMR (400MHz, CDCl₃): δ 8.38 (d, 1H, 8.3 Hz), 7.69 (d, 2H, 8.9 Hz), 7.58-7.63 (m,3H), 7.42-7.48 (m, 2H), 7.29-7.34 (m, 1H), 7.19-7.21 (m, 2H), 7.04 (d,2H, 8.9 Hz), 3.84-3.88 (m, 1H), 3.56-3.68 (m, 4H), 2.02 (br, 2H, —OH);LC/MS: m/z=429.1 [M+H]⁺ (Calc: 428.4).

Example 37

(a) A mixture of compound 160 (Accela ChemBio, 0.2 g, 1.0 eq), compound78 (1.1 eq), CuI (0.2 eq), K₂CO₃ (3 eq), and N,N-dimethylglycine(Aldrich, 0.1 eq) in DMF (10 mL) was heated at 165° C. for 2 hours undermicrowave. The mixture was poured into water/EtOAc (40 mL/200 mL). Theorganic layer was washed with brine, concentrated and purified by column(silica gel, CHCl₃/hexane 1/1) to afford compound 161 as a brown solid(LC/MS: m/z=355.4 [M+H]⁺ (Calc: 354.3), which was dissolved intrifluoroacetic acid (10 mL), and then added 0.5 g of compound 162 atroom temperature. The resulting mixture was shaken at 70° C. for 24hours. The solvent was evaporated and the residues was diluted withwater (40 mL)/DCM (100 mL), and neutralized to pH˜10 with 1N NaOHaqueous at 0° C. The organic layer was separated and purified by column(silica gel, CHCl₃/MeOH 10/0.2) to afford compound 163 as a white solid(0.15 g, 30% in two steps): ¹H-NMR (400 MHz, CDCl₃): δ 10.1 (s, 1H),8.82 (d, 1H, 1.1 Hz), 8.46 (d, 1H, 5.5 Hz), 8.19 (dd, 1H, 0.9 & 5.3 Hz),7.98 (s, 1H), 7.59-7.62 (m, 2H), 7.47-7.51 (m, 2H), 7.19-7.22 (m, 2H),7.1-7.13 (m, 2H).

(b) NaBH₄ (0.25 g) was added to a solution of compound 163 (0.12 g) in10 mL of EtOH at room temperature. The mixture was shaken at roomtemperature for 3 hours, quenched with water, extracted with EtOAc (30mL), concentrated and purified by column (CHCl₃/MeOH 10/0.5) to give thetitle compound 164 as a white solid: ¹H-NMR (400 MHz, CD₃OD): δ 8.8 (s,1H), 8.23 (d, 1H, 5.5 Hz), 7.64-7.82 (m, 6H), 7.32 (d, 2H, 8.9 Hz), 7.24(d, 2H, 8.3 Hz), 4.89 (s, 2H); LC/MS: m/z=385.1 [M+H]⁺ (Calc: 384.4).

Example 38

n-Buli (2.5N 0.8 mL in hexanes) was added to a solution of compound 94in 15 mL of THF at −30° C. The resulting yellow suspension was stirredand allowed to warm to 0° C. over 1 hour. After cooling to −30° C.,compound 163 (0.5 g, in 10 mL THF) was added, the resulting mixture waswarmed to room temperature over 40 min, and kept at room temperatureover night. The reaction mixture was quenched with water, extracted withCHCl₃, and purified by column to get compound 165 as a brown oil (LC/MS:m/z=381.3 [M+H]⁺ (Calc: 380.3), which was dissolved in t-BuOH/water(1/1, 40 mL) and treated with AD-mix-β (2 g) at 0° C. The reactionmixture was warmed to room temperature over night and heated to 35° C.for 24 hours. Water (50 mL) and EtOAc (200 mL) were added to thereaction mixture. The organic layer was separated, washed with brine,concentrated and purified by column (silica gel, EtOAc/MeOH 10/1) togive the title compound 166 as a white solid (0.15 g, 25% in two steps):¹H-NMR (400 MHz, CD₃OD): δ 8.68 (s, 1H), 8.09 (d, 1H, 5.5 Hz), 7.73 (d,1H, 5.3 Hz), 7.55-7.65 (m, 4H), 7.22 (d, 2H, 8.9 Hz), 7.14 (d, 2H, 8.3Hz), 5.0 (t, 6.0 Hz), 3.79 (d, 2H, 5.8 Hz); LC/MS: m/z=415.1 [M+H]⁺(Calc: 414.4).

Example 39

Compound 170 (white solid) was prepared following the proceduredescribed for preparing compound 105 in Example 24: ¹H-NMR (400 MHz,CD₃OD): δ 8.68 (d, 1H, 1.1 Hz), 8.08 (d, 1H, 5.7 Hz), 7.64-7.67 (m, 3H),7.55-7.58 (m, 3H), 7.21-7.24 (m, 2H), 7.07-7.19 (m, 2H), 3.83-3.88 (m,1H), 3.43-3.51 (m, 2H), 2.97-3.04 (m, 1H), 2.76-2.83 (m, 1H); LC/MS:m/z=386.2 [M+H]⁺ (Calc: 385.4).

Example 40

Compound 175 (white solid) was prepared following the proceduredescribed for preparing compound 105 in Example 24: ¹H-NMR (400 MHz,CD₃OD): δ 8.5-8.54 (m, 2H), 8.13 (s, 1H), 7.61-7.7 (m, 5H), 7.27-7.31(m, 2H), 7.1-7.14 (m, 2H), 3.83-3.91 (m, 1H), 3.45-3.54 (m, 2H),2.99-3.14 (m, 1H), 2.56-3.01 (m, 1H); LC/MS: m/z=386.2 [M+H]⁺ (Calc:385.4).

Example 41

(a) NaH (0.1 g, 60% dispersion in mineral oil) was added to a mixture ofcompound 71 (0.3 g, 1 mmol) and compound 176 (1.0 mmol) in 4 mL of DMFat 0° C. The reaction mixture was warmed to room temperature over 2 h,and quenched with water (10 mL), and extracted with EtOAc (100 mL). Theorganic layer was washed with brine, concentrated under vacuum andpurified by column (CHCl₃/hexanes 9/1) to afford compound 177 as ayellow oil (0.3 g): ¹H-NMR (400 MHz, CDCl₃): δ 7.81-7.83 (m, 1H), 7.62(d, 2H, 8.9 Hz), 7.44-7.5 (m, 2H), 7.21 (d, 1H, 3.1 Hz), 7.04-7.11 (m,6H), 6.55 (d, 1H, 3.1 Hz), 4.28-4.33 (m, 2H), 2.85 (t, 1H, 7.0 Hz), 2.63(q, 4H, 7.3 Hz), 1.04 (t, 6H, 7.2 Hz); LC/MS: m/z=403.3 [M+H]⁺ (Calc:402.5).

(b) Compound 58 (2N in DCM, 3 mL) was added to a solution of compound177 (0.5 g) in 10 mL of Et₂O and 20 mL of DCM at 0° C. The reactionmixture was shaken at 0° C. for 1.5 hours and, then, concentrated undervacuum. The residue was dissolved in THF (20 mL) and then NH₃ (˜7N inMeOH) was added at 0° C. The reaction mixture was shaken at roomtemperature for 36 hours. The solvents were evaporated under vacuum, andthe residue was purified by column (CHCl₃/MeOH 10/1) to give compound178 as a white solid (0.25 g): ¹H-NMR (400 MHz, CD₃OD): δ 8.81 (s, 1H),8.49-8.51 (m, 1H), 7.55 (d, 2H, 8.9 Hz), 7.44-7.5 (m, 2H), 6.94-6.99 (m,6H), 4.23 (t, 2H, 7.2 Hz), 2.83 (t, 1H, 7.2 Hz), 2.54 (q, 4H, 7.3 Hz),0.94 (t, 6H, 7.2 Hz); LC/MS: m/z=474.1 [M+H]⁺ (Calc: 473.5).

(c) NaBH₄ (40 mg) was added to a solution of compound 178 (100 mg) inEtOH/THF (2 mL/2 mL) at room temperature, and the mixture was shaken atroom temperature for 2 hours. The reaction was quenched with water,extracted with EtOAc (30 mL), concentrated, and purified by column(CHCl₃/MeOH 7/1) to give compound 179 as a white solid (70 mg, 70%):¹H-NMR (400 MHz, CD₃OD): δ 8.01 (s, 1H), 7.66 (d, 2H, 8.9 Hz), 7.46-7.48(m, 1H), 7.36-7.37 (m, 1H), 7.03-7.14 (m, 6H), 5.36 (s, 1H), 4.3 (t, 2H,7.2 Hz), 2.89 (t, 1H, 7.2 Hz), 2.66 (q, 4H, 7.3 Hz), 1.08 (t, 6H, 7.2Hz); LC/MS: m/z=476.2 [M+H]⁺ (Calc: 475.5).

Example 42

(a) Compound 71 (1.6 g, 5 mmol in 10 mL of THF) was added to a solutionof ethylmagnesium bromide (1.0 M in THF, 8 mL, Aldrich) at roomtemperature under argon. The resulting mixture was stirred at roomtemperature for 2 hours. The reaction mixture was cooled to −20° C., anda solution of compound 72 (0.6 g, in 20 mL of THF) was added to thecooled reaction mixture over 5 minutes. The reaction mixture was allowedto warm to room temperature over night. The reaction was quenched withwater (40 mL), and extracted with EtOAc (2×200 mL). The combined organiclayer was washed with brine, concentrated and purified by column to getcompound 180 as a white solid (0.8 g): ¹H-NMR (400 MHz, CDCl₃): δ 8.01(br, 1H, NH), 7.8 (s, 1H), 7.64 (d, 2H, 8.9 Hz), 7.43-7.45 (m, 2H),7.06-7.13 (m, 7H), 6.09-6.18 (m, 1H), 5.2-5.26 (m, 1H), 5.11-5.15 (m,1H), 3.59-3.62 (m, 2H).

(b) Compound 181 was prepared according to the same procedure used forpreparing compound 177 in Example 41: ¹H-NMR (400 MHz, CDCl₃): δ 7.68(s, 1H), 7.52 (d, 2H, 8.9 Hz), 7.28-7.35 (m, 2H), 6.94-7.01 (m, 6H),6.88 (s, 1H), 5.95-6.04 (m, 1H), 5.08-5.11 (m, 1H), 4.98-5.02 (m, 1H),4.11-4.15 (m, 2H), 3.44-3.48 (m, 2H), 2.74-2.81 (m, 2H), 2.55 (q, 4H,7.2 Hz), 0.98 (t, 6H, 7.3 Hz).

(c) Compound 182 was prepared following the same procedure used forpreparing compound 76 in Example 20: ¹H-NMR (400 MHz, CD₃OD): δ 7.76 (s,1H), 7.55 (d, 2H, 8.9 Hz), 7.38-7.45 (m, 2H), 7.13 (s, 1H), 6.94-7.05(m, 6H), 4.56 (t, 2H, 6.5 Hz), 3.84-3.91 (m, 1H), 3.42-3.58 (m, 4H),3.11-3.18 (m, 4H), 2.94-2.98 (m, 1H), 2.72-2.78 (m, 1H), 1.18 (t, 6H,7.3 Hz); LC/MS: m/z=477.3 [M+H]⁺ (Calc: 476.6).

Example 43

(a) Compound 184 was prepared following the procedure used for preparingcompound 177 in Example 41: LC/MS: m/z=430.4 [M+H]⁺ (Calc: 429.5).

(b) Compound 185 was prepared following the procedure used for preparingcompound 76 in Example 20: LC/MS: m/z=464.2 [M+H]⁺ (Calc: 463.5).

(c) A solution of compound 185 (0.1 g) in 3 mL of NH₃ (˜7N in MeOH) wasshaken at room temperature for 18 hours. The solvent was evaporatedunder vacuum, and the residue was purified by column (silica gel,EtOAc/MeOH 10/1) to give compound 186 as a white solid (60 mg): ¹H-NMR(400 MHz, DMSO-d₆): δ 7.72 (s, 1H), 7.61 (d, 2H, 8.9 Hz), 7.28-7.45 (m,3H), 7.16-7.21 (m, 3H), 6.97-7.05 (m, 5H), 4.68 (s, 2H), 4.44-4.52 (m,2H), 3.64-3.69 (m, 1H), 2.82-2.86 (m, 1H), 2.57-2.61 (m, 1H); LC/MS:m/z=435.1 [M+H]⁺ (Calc: 434.5).

Example 44

(a) Compound 189 was prepared according the same procedure used forpreparing compound 49 in Example 16 and was obtained as a white solid:¹H-NMR (400 MHz, CDCl₃): δ 7.83 (d, 1H, 8.6 Hz), 7.74 (d, 1H, 8.9 Hz),7.58-7.64 (m, 3H), 7.46 (d, 1H, 2.6 Hz), 7.37 (d, 1H, 3.2 Hz), 7.21-7.31(m, 5H), 6.75 (dd, 1H, 0.6 & 3.3 Hz).

(b) A mixture of compound 189 (0.15 g, 1.0 eq) and compound 190 (2.0 eq)was shaken at room temperature for 2 hours. The reaction mixture waspurified by column (EtOAc/Hexanes 10/3) to give compound 191 as acolorless oil (0.12 g, 57%): LC/MS: m/z=557.0 [M+Na]⁺ (Calc: 534.4).

(c) A solution of compound 191 (0.1 g) in 2 mL of NH₃ (˜7N in MeOH) wasshaken at room temperature for 3 days. The solvent was removed undervacuum, and the residue was purified by column (silica gel, CHCl₃/MeOH10/1) to give compound 192 as a white solid (90 mg): ¹H-NMR (400 MHz,CD₃OD): δ 7.89 (d, 1H, 8.9 Hz), 7.83 (d, 1H, 7.9 Hz), 7.5-7.6 (m, 3H),7.46 (d, 1H, 2.6 Hz), 7.4-7.43 (m, 1H), 7.26-7.31 (m, 3H), 7.12-7.17 (m,1H), 7.04-7.08 (m, 1H); LC/MS: m/z=542.1 [M+Na]⁺ (Calc: 519.4).

(d) Compound 193 was prepared according the same procedure used forpreparing compound 179 and was obtained as a white solid: ¹H-NMR (400MHz, CD₃OD): δ 7.89 (d, 1H, 8.7 Hz), 7.76 (d, 1H, 7.9 Hz), 7.57 (d, 2H,8.9 Hz), 7.42-7.45 (m, 3H), 7.24-7.28 (m, 3H), 7.12-7.17 (m, 1H),7.04-7.08 (m, 1H), 5.29 (s, 1H); LC/MS: m/z=474.1 [M+Na]⁺ (Calc: 451.4).

Example 45

(a) Compound 194 was prepared according the same procedure used forpreparing compound 49 in Example 16 and was obtained as a colorless oil:LC/MS: m/z=355.2 [M+H]⁺ (Calc: 354.3).

(b) Compound 195 was prepared according the same procedure used forpreparing compound 179 in Example 41 and was obtained as a white solid:¹H-NMR (400 MHz, CD₃OD): δ 8.49 (s, 1H), 8.15 (dd, 1H, 2.4 & 8.5 Hz),7.87 (d, 1H, 7.9 Hz), 7.63 (d, 2H, 8.9 Hz), 7.53-7.56 (m, 2H), 7.38 (d,2H, 8.9 Hz), 7.14-7.26 (m, 3H), 5.4 (s, 1H); LC/MS: m/z=450.1 [M+Na]⁺(Calc: 427.4).

Example 46

Compound 196 was prepared following the same procedure used forpreparing compound 47 in Example 11, and purified by HPLC to give theTFA-salt as a white solid: ¹H-NMR (400 MHz, DMSO-d₆): δ 8.55 (s, 1H),8.23 (dd, 1H, 2.1 & 8.5 Hz), 7.88 (br, 3H, NH₃), 7.66 (d, 1H, 7.4 Hz),7.6 (d, 2H, 8.9 Hz), 7.55 (s, 1H), 7.53 (d, 1H, 8.1 Hz), 7.38 (d, 2H,8.9 Hz), 7.28 (d, 1H, 8.8 Hz), 7.19 (dt, 1H, 1.1 & 8.1 Hz), 7.1-7.14 (m,1H), 5.3 (br, 1H, —OH), 3.56-3.61 (m, 1H), 3.44-3.48 (m, 1H), 3.34-3.38(m, 1H), 2.98 (d, 2H, 6.8 Hz); LC/MS: m/z=428.1 [M+H] (Calc: 427.4).

Example 47

(a) NaH (0.1 g, 60% dispersion in mineral oil) was added to a mixture ofcompound 180 (0.3 g, 1 mmol) and compound 197 (1.3 mmol) in 4 mL of DMFat 0° C. The reaction mixture was warmed to room temperature over 2hours and then quenched with water (10 mL) and extracted with EtOAc (100mL). The organic layer was washed with brine and concentrated to affordcrude product 198 [LC/MS: m/z=502.2 [M+H]⁺ (Calc: 501.7)], which wassuspended in 40 mL of i-PrOH/water (25 mL/15 mL) at room temperature.Methanesulfonamide (1 mmol) and Ad-mix-α (3.0 g) were added to the abovesolution. The reaction mixture was stirred at room temperature for 16hours and then diluted with EtOAc (200 mL) and washed with water (40mL). The organic layer was washed with brine, dried over Na₂SO₄,concentrated and purified by silica gel chromatography (EtOAc/hexanes1/1) to give compound 199 as a brown oil (0.2 g): ¹H-NMR (400 MHz,CDCl₃): δ 7.84 (d, 1H, 1.5 Hz), 7.69 (d, 1H, 8.9 Hz), 7.53 (dd, 1H, 1.7& 8.6 Hz), 7.48 (d, 1H, 8.6 Hz), 7.12-7.17 (m, 7H), 4.32 (t, 2H, 6.7Hz), 4.14-4.19 (m, 1H), 4.02 (t, 2H, 5.6 Hz), 3.85-3.89 (m, 1H),3.68-3.72 (m, 1H), 2.99-3.12 (m, 2H), 2.0 (br, 2H, —OH), 0.93 (s, 9H),0.01 (s, 6H).

(b) A mixture of compound 199 (100 mg) in 10 mL of MeOH and 1 mL of HCl(5N aqueous) was shaken at room temperature for 3 hours. The reactionmixture was diluted with EtOAc (100 mL), and neutralized with 1N NaOH(aqueous) to pH˜10. The organic layer was washed with brine, dried overNa₂SO₄, concentrated and purified by silica gel chromatography(EtOAc/MeOH 10/1) to give compound 200 as a white solid (50 mg): ¹H-NMR(400 MHz, CDCl₃): δ 7.78 (d, 1H, 1.5 Hz), 7.67 (d, 1H, 8.9 Hz), 7.53(dd, 1H, 1.7 & 8.6 Hz), 7.48 (d, 1H, 8.6 Hz), 7.38 (dd, 1H, 1.7 & 8.6Hz), 7.23-7.27 (m, 3H), 7.19 (s, 1H), 7.06-7.14 (m, 4H), 4.88 (t, 2H,5.3 Hz), 4.56 (d, 1H, 5.0 Hz), 4.53 (t, 1H, 5.7 Hz), 4.17 (t, 2H, 5.4Hz), 3.69-3.74 (m, 3H), 3.34 (br, 1H), 2.85-2.93 (m, 1H), 2.65-2.71 (m,1H); LC/MS: m/z=422.1 [M+H]⁺ (Calc: 421.5).

Example 48

The two chiral isomers of compound 60 (prepared in Example 16) wereseparated by Regis Technologies Inc. (through chiral-HPLC; column name:(S,S) Whelk-O, Mobile phase: Methanol). The two isomers were assignedbased upon rotation, and similar compounds in the literature (Scott E.Denmark and Yu Fan, J. Org. Chem. 70(24): 9667-9677 (2005)):

(S)-2-(1-(4-(3-Cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide(60-S): first collection, white solid. ¹H-NMR (400 MHz, CD₃OD): δ 7.91(d, 1H, 8.8 Hz), 7.84 (dd, 1H, 0.87, 7.8 Hz), 7.66-7.69 (m, 3H),7.53-7.56 (m, 2H), 7.45-7.48 (m, 1H), 7.35-7.38 (m, 2H), 7.15-7.25 (m,2H), 5.38 (br, 1H); LC/MS: m/z=474.3 [M+Na]⁺ (Calc: 451.4).

(R)-2-(1-(4-(3-Cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide(60-R): second collection, white solid. ¹H-NMR (400 MHz, CD₃OD): δ 7.9(d, 1H, 8.9 Hz), 7.84 (d, 1H, 0.87, 7.9 Hz), 7.64-7.68 (m, 3H),7.52-7.55 (m, 2H), 7.45-7.48 (m, 1H), 7.35-7.38 (m, 2H), 7.15-7.25 (m,2H), 5.38 (br, 1H); LC/MS: m/z=474.3 [M+Na]⁺ (Calc: 451.4).

Example 49

Compounds of the invention have been tested in the FLIPR^(TETRA)® orFLIPR® sodium dye assay with KCl assay and electrophysiology (EP) assayfor sodium channel blocking activity, which are described in detailabove. Representative values are presented in TABLE 2.

TABLE 2 Evaluation of the tested compounds as sodium channel (Na_(v))blockers FLIPR EP Na_(v)1.7 Na_(v)1.7 COMPOUND IC₅₀ (μM) ± SEM Ki (μM)2-amino-3-[7-(4-phenoxyphenyl)-1H-indol-3- 0.151 ± 0.016 0.83yl]propan-1-ol (22) 2-amino-3-[2-(4-phenoxyphenyl)-1H-indol-3- 0.240 ±0.023 yl]propionamide (28) 2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-0.278 ± 0.061 0.04 yl]propionamide (35)2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3- 0.296 ± 0.087 0.36yl]propan-1-ol (10) 2-amino-N-(2-hydroxyethyl)-3-[1-(4- 0.364 ± 0.112phenoxyphenyl)-1H-indol-3-yl]-propionamide (37)2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3- 0.389 ± 0.081 0.26yl]propan-1-ol (34) 2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3- 0.399 ±0.024 0.67 yl]propionamide (8)2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3- 0.481 ± 0.042 yl]propionicacid ethyl ester (7) 2-methanesulfonylamino-3-[1-(4- 1.012 ± 0.162phenoxyphenyl)-1H-indol-3-yl]-propionamide (39)2-tert-butoxycarbonylamino-3-[6-(4- 1.931 ± 0.228phenoxyphenyl)-1H-indol-3-yl]propionic acid (17)2-amino-3-[6-(4-phenoxyphenyl)-1H-indol-3- 2.054 ± 0.094 yl]propionamide(15) 2-tert-butoxycarbonylamino-3-[6-(4- 2.524 ± 0.663phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester (16)2-nitro-3-[5-(4-phenoxyphenyl)-1H-indol-3- 5.142 ± 0.954 yl]propionicacid ethyl ester (6) 2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3- >20yl]propionic acid (9) (S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-0.213 ± 0.052 0.16 1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile (47)(R)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol- 0.304 ± 0.046 0.291-yl]phenoxy}-2-(trifluoromethyl)benzonitrile (44)(S)-5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H- 0.715 ± 0.126indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile (46)(S)-4-{[3-(2-dimethylaminoethyl)-1-(4- 1.902 ± 0.636 1.31phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin- 2-one (45)(S)-2-amino-3-[3-(2-dimethylaminoethyl)-1-(4- 3.816 ± 1.019 1.31phenoxyphenyl)-1H-indol-5-yl]propan-1-ol (48)2-(1-(4-phenoxyphenyl)-1H-indol-3- 0.684 ± 0.041 yl)ethanamine (43)5-{4-[3-(1,2-dihydroxyethyl)-1H-indol-1- 0.260 ± 0.009yl]phenoxy}-2-(trifluoromethyl)benzonitrile (51)(S)-5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1- 0.210 ± 0.035 0.07yl]phenoxy}-2-(trifluoromethyl)benzonitrile (54)5-{4-[3-(2-ethoxyoxalyl)-1H-indol-1-yl]phenoxy}- 0.740 ± 0.1482-(trifluoromethyl)-benzonitrile (50)(S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol- 0.383 ± 0.081 0.051-yl]phenoxy}benzonitrile (57)2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)- 3.539 ± 0.459phenyl)-1H-indol-3-yl)-2-oxoacetamide (59)2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)- 0.224 ± 0.038 0.40phenyl)-1H-indol-3-yl)-2-hydroxyacetamide (60) Methyl3-(2-amino-1-hydroxy-2-oxoethyl)-1-(4-(3- 0.536 ± 0.129 1.91cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H- indole-6-carboxylate (65)(S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)- 0.572 ± 0.137phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2- oxoacetamide (68)2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)- 0.732 ± 0.113 2.67phenyl)-1H-indol-3-yl)-N-((S)-2,3- dihydroxypropyl)-2-hydroxyacetamide(69) (2S,2′S)-3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H- 0.500 ± 0.091 0.92indole-1,3-diyl)bis(propane-1,2-diol) (74)(S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1- 0.501 ± 0.089yl)phenoxy)benzonitrile (76)(R)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1- 0.480 ± 0.087yl)phenoxy)benzonitrile (77) (S)-3-(1-(4-((5-(trifluoromethyl)pyridin-2-0.257 ± 0.067 yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol (83)(S)-3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)- 0.524 ± 0.0851H-indol-3-yl)propane-1,2-diol (80)(S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N- 0.865 ± 0.058(4-fluorophenyl)-N-methylbenzenesulfonamide (90)(S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N- 1.886 ± 0.164(4-fluorophenyl)benzenesulfonamide (92)(R)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)- >20phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2- oxoacetic acid (98)(S)-3-(2,3-dihydroxypropyl)-1-(4-(4- 1.654 ± 0.438fluorophenoxy)phenyl)-1H-indole-6-carbonitrile (105)(S)-3-(2,3-dihydroxypropyl)-1-(4-(4- 2.452 ± 0.542fluorophenoxy)phenyl)-1H-indole-5-carbonitrile (110)(S)-3-(2,3-dihydroxypropyl)-1-(4-(4- 0.474 ± 0.133fluorophenoxy)phenyl)-1H-indole-7-carbonitrile (115)(S)-3-(2,3-dihydroxypropyl)-1-(4-(4- 0.262 ± 0.066fluorophenoxy)phenyl)-1H-indole-4-carbonitrile (120)(S)-3-(2,3-dihydroxypropyl)-1-(4-(4- 0.222 ± 0.036 0.30fluorophenoxy)phenyl)-1H-indole-4-carboxamide (122)(S)-3-(2,3-dihydroxypropyl)-1-(4-(4- 4.923 ± 0.822fluorophenoxy)phenyl)-1H-indole-6-carboxamide (123)(S)-3-(2,3-dihydroxypropyl)-1-(4-(4- 3.335 ± 0.495fluorophenoxy)phenyl)-1H-indole-4-carboxylic acid (129)5-4-(4-(1,2-dihydroxyethyl)-3-((R)-2,3- >20dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2- (trifluoromethyl)benzonitrile(139) 5-4-(4-(1,2-dihydroxyethyl)-3-((S)-2,3- 1.973 ± 0.494dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2- (trifluoromethyl)benzonitrile(141) N-(2-hydroxyethyl)-1-(4-phenoxyphenyl)-1H- 0.160 ± 0.049indazole-3-carboxamide (144)1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide 0.326 ± 0.043 (145)N-hydroxy-1-(4-phenoxyphenyl)-1H-indazole-3- 8.068 ± 0.484 carboxamide(146) 5-fluoro-1-(4-(4-(trifluoromethyl)phenoxy)phenyl)- 6.967 ± 0.9341H-indazole-3-carboxamide (150)1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)- 0.602 ± 0.053phenyl)-1H-indazole-3-carboxamide (152)1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)- 0.362 ± 0.060 0.251H-indazole-3-carboxamide (155) 1-(4-(4-cyanophenoxy)phenyl)-N-(2,3-0.431 ± 0.059 0.93 dihydroxypropyl)-1H-indazole-3-carboxamide (159)1-(4-4-(trifluoromethyl)phenoxy)phenyl)-1H- 0.345 ± 0.027pyrrolo[2,3-c]pyridin-3-yl)methanol (164)(R)-1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)- 0.486 ± 0.024 0.641H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol (166)(S)-3-(1-(4-(4-fluorophenoxy)phenyl)-1H- 1.378 ± 0.542pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol (170)(S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2- 0.549 ± 0.197 0.17b]pyridin-1-yl)phenoxy)benzonitrile (175)N,N-diethyl-2-(5-(4-(4-fluorophenoxy)phenyl)-1H- 0.895 ± 0.154indol-1-yl)ethanamine (177) 2-(1-(2-(diethylamino)ethyl)-5-(4-(4- 1.030± 0.076 fluorophenoxy)phenyl)-1H-indol-3-yl)-2- oxoacetamide (178)2-(1-(2-(diethylamino)ethyl)-5-(4-(4- 0.912 ± 0.079 0.27fluorophenoxy)phenyl)-1H-indol-3-yl)-2- hydroxyacetamide (179)(S)-3-(1-(2-(diethylamino)ethyl)-5-(4-(4- 1.065 ± 0.026fluorophenoxy)phenyl)-1H-indol-3-yl)propane- 1,2-diol (182)(S)-2-(3-(2,3-dihydroxypropyl)-5-(4-(4- 0.717 ± 0.042fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide (186)2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)- 0.475 ± 0.065phenyl)-1H-indol-3-yl)-3,3,3-trifluoro-2- hydroxypropanamide (192)2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)- 0.414 ± 0.026phenyl-1H-indol-3-yl)-2-hydroxyacetamide (193)2-hydroxy-2-(1-(4-((5-(trifluoromethyl)pyridin-2- 0.276 ± 0.011yl)oxy)phenyl)-1H-indol-3-yl)acetamide (195)(S)-2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2- 0.340 ± 0.023yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol (196)(S)-3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2- 0.273 ± 0.061hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol (200)

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference herein in their entirety.

1-91. (canceled)
 92. A method for treating a condition in a mammal,wherein the condition is stroke, neuronal damage resulting from headtrauma, epilepsy, seizures, general epilepsy with febrile seizures,severe myoclonic epilepsy in infancy, neuronal loss following global andfocal ischemia, migraine, familial primary erythromelalgia, paroxysmalextreme pain disorder, cerebellar atrophy, ataxia, distonia, tremor,mental retardation, autism, a neurodegenerative disorder, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, said method comprising administering to the mammalidentified as in need thereof an effective amount of a compound ofFormula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: Z¹ is CR² or N, Z² is CR³ or N, Z³ is CR⁴ or N, Z⁴ is CR⁵ or N,and Z⁵ is CR⁶ or N, provided that Z², Z³, Z⁴, and Z⁵ are not all N atthe same time; G is G¹, G², or G³, wherein G¹ is

G² is

G³ is

m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; r is 0 or 1; s is 1 or 2;provided that when r is 1, then s is 1; R⁷ is selected from the groupconsisting of a) —C(═O)NR^(1i)R¹¹, wherein R¹⁰ and R¹¹ are eachindependently selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, and dialkylaminoalkyl; b) —C(═O)OR¹², wherein R¹² isselected from the group consisting of hydrogen, alkyl, hydroxyalkyl,alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,and dialkylaminoalkyl; c) —(CH₂)_(n)OR¹³, wherein n is 1-5 and R¹³ ishydrogen; and d) hydrogen; R⁸ and R⁹ are each independently selectedfrom the group consisting of hydrogen, alkyl, alkylsulfonyl,alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionallysubstituted arylcarbonyl; or NR⁸R⁹ is —NO₂; or R⁹ is hydrogen, R⁷ is—(CH₂)_(n)OR¹³, R⁸ and R¹³ together form a bridge —C(═O)— to form aheterocyclic ring, n is 1-5, and m is 1, 2 or 3; R^(7a) is selected fromthe group consisting of a) —(CH₂)_(q)OH, wherein q is 1, 2, 3, 4, or 5;b) —C(═O)OR^(12a), wherein R^(12a) is selected from the group consistingof hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; andc) hydrogen; R^(8a) is hydrogen or a bond; provided that when R^(7a) ishydrogen, then R^(8a) is hydrogen; R^(7b) and R^(8b) are are eachindependently selected from the group consisting of hydrogen, alkyl,alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, andoptionally substituted arylcarbonyl; R^(9b) is hydrogen, alkyl,haloalkyl, haloalkoxyalkyl, alkoxyalkyl, cyanoalkyl, or hydroxyalkyl;one of R¹, R², R³, R⁴, R⁵, and R⁶ is A, wherein A is

wherein A¹ is aryl or heteroaryl, any of which is optionallysubstituted; X is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NR²⁷—, —N(R²⁸)SO₂—, or—SO₂N(R²⁹)—, wherein R²⁷, R²⁸, and R²⁹ are each independently hydrogenor alkyl; and R¹⁴ and R¹⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; R¹, when not A, is hydrogen, alkyl,hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonylalkyl, (alkylaminocarbonyl)alkyl, or(dialkylaminocarbonyl)alkyl; and R², R³, R⁴, R⁵, and R⁶, when not A, areeach independently selected from the group consisting of hydrogen;optionally substituted alkyl, optionally substituted alkenyl, oroptionally substituted alkynyl; halogen; hydroxy; cyano; amino;alkylamino; dialkylamino; alkoxy; aminocarbonyl; alkylaminocarbonyl;dialkylaminocarbonyl; alkylcarbonylamino; alkylcarbonyloxy; carboxy;aminosulfonyl; alkylsulfonylamino; and alkoxycarbonyl.
 93. The method ofclaim 92, wherein said compound is2-amino-3-[7-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,2-amino-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,2-amino-N-(2-hydroxyethyl)-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide,2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid,2-methanesulfonylamino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide,2-tert-butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionicacid, 2-amino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,2-tert-butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionicacid ethyl ester, 2-nitro-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionicacid ethyl ester,5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,4-{[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one,2-amino-3-[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol,2-(1-(4-phenoxyphenyl)-1H-indol-3-yl)ethanamine,5-{4-[3-(1,2-dihydroxyethyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)-benzonitrile,5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,5-{4-[3-(2-ethoxyoxalyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)-benzonitrile,2-nitro-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,2-amino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,2-nitro-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,2-amino-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,2-nitro-3-[1-(4-phenoxyphenyl)-1H0indol-3-yl]propionic acid ethyl ester,2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}benzonitrile,(S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,(R)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,(S)-5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,(S)-4-{[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one,(S)-2-amino-3-[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol,(S)-5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,(S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}benzonitrile,2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-oxoacetamide,2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,methyl3-(2-amino-1-hydroxy-2-oxoethyl)-1-(4-(3-cyano-4-(trifluoromethyl)-phenoxy)phenyl)-1H-indole-3-carboxylate,2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-oxoacetamide,2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-hydroxyacetamide,3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H-indole-1,3-diyl)bis(propane-1,2-diol),4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-N-methylbenzenesulfonamide,4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-benzenesulfonamide,2-(1-(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2-oxoaceticacid,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carbonitrile,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-5-carbonitrile,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-7-carbonitrile,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carbonitrile,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxamide,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carboxamide,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxylicacid,5-(4-(4-(1,2-dihydroxyethyl)-3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,(N)-(2-hydroxyethyl)-1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,N-hydroxy-1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,5-fluoro-1-(4-(4-trifluoromethyl)phenoxy)phenyl)-1H-indazole-3-carboxamide,1-(4-(3-cyano-(4-trifluoromethyl)phenoxy)phenyl)-1H-indazole-3-carboxamide,1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indazole-3-carboxamide,1-(4-(4-cyanophenoxy)phenyl)-N-(2,3-dihydroxypropyl)-1H-indazole-3-carboxamide,(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methanol,1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol,3-(1-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol,4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenoxy)benzonitrile,2-(1-(2-diethylamino)ethyl-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)-2-oxoacetamide,2-(1-(2-(diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,3-(1-(2-diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,2-(3-(2,3-dihydroxypropyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide,2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanamide,2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,2-hydroxy-2-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)acetamide,2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol,3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol,(S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-oxoacetamide,2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N—((S)-2,3-dihydroxypropyl)-2-hydroxyacetamide,(2S,2′S)-3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H-indole-1,3-diyl)bis(propane-1,2-diol),(S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,(R)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,(S)-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,(S)-3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,(S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-N-methylbenzenesulfonamide,(S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-benzenesulfonamide,(R)-2-(1-(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2-oxoaceticacid,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carbonitrile,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-5-carbonitrile,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-7-carbonitrile,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carbonitrile,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxamide,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carboxamide,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxylicacid,5-(4-(4-(1,2-dihydroxyethyl)-3-((R)-2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,5-(4-(4-(1,2-dihydroxyethyl)-3-((S)-2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,(R)-1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol,(S)-3-(1-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol,(S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenoxy)benzonitrile,(S)-3-(1-(2-diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,(S)-2-(3-(2,3-dihydroxypropyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide,(S)-2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol,(S)-3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol,(S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,(R)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 94. Amethod for providing local anesthesia in a subject, comprisingadministering to the subject identified as in need thereof an effectiveamount of a compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: Z¹ is CR² or N, Z² is CR³ or N, Z³ is CR⁴ or N, Z⁴ is CR⁵ or N,and Z⁵ is CR⁶ or N, provided that Z², Z³, Z⁴, and Z⁵ are not all N atthe same time; G is G¹, G², or G³, wherein G¹ is

G² is

and G³ is

m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; r is 0 or 1; s is 1 or 2;provided that when r is 1, then s is 1; R⁷ is selected from the groupconsisting of a) —C(═O)NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are eachindependently selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, and dialkylaminoalkyl; b) —C(═O)OR¹², wherein R¹² isselected from the group consisting of hydrogen, alkyl, hydroxyalkyl,alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,and dialkylaminoalkyl; c) —(CH₂)_(n)OR¹³, wherein n is 1-5 and R¹³ ishydrogen; and d) hydrogen; R⁸ and R⁹ are each independently selectedfrom the group consisting of hydrogen, alkyl, alkylsulfonyl,alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionallysubstituted arylcarbonyl; or NR⁸R⁹ is —NO₂; or R⁹ is hydrogen, R⁷ is—(CH₂)_(n)OR¹³, R⁸ and R¹³ together form a bridge —C(═O)— to form aheterocyclic ring, n is 1-5, and m is 1, 2 or 3; R^(7a) is selected fromthe group consisting of a) —(CH₂)_(q)OH, wherein q is 1, 2, 3, 4, or 5;b) —C(═O)OR^(12a), wherein R^(12a) is selected from the group consistingof hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; andc) hydrogen; R^(8a) is hydrogen or a bond; provided that when R^(7a) ishydrogen, then R^(8a) is hydrogen; R^(7b) and R^(8b) are are eachindependently selected from the group consisting of hydrogen, alkyl,alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, andoptionally substituted arylcarbonyl; R^(9b) is hydrogen, alkyl,haloalkyl, haloalkoxyalkyl, alkoxyalkyl, cyanoalkyl, or hydroxyalkyl;one of R¹, R², R³, R⁴, R⁵, and R⁶ is A, wherein A is

wherein A¹ is aryl or heteroaryl, any of which is optionallysubstituted; X is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NR²⁷—, —N(R²⁸)SO₂—, or—SO₂N(R²⁹)—, wherein R²⁷, R²⁸, and R²⁹ are each independently hydrogenor alkyl; and R¹⁴ and R¹⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; R¹, when not A, is hydrogen, alkyl,hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminocarbonylalkyl, (alkylaminocarbonyl)alkyl, or(dialkylaminocarbonyl)alkyl; and R², R³, R⁴, R⁵, and R⁶, when not A, areeach independently selected from the group consisting of hydrogen;optionally substituted alkyl, optionally substituted alkenyl, oroptionally substituted alkynyl; halogen; hydroxy; cyano; amino;alkylamino; dialkylamino; alkoxy; aminocarbonyl; alkylaminocarbonyl;dialkylaminocarbonyl; alkylcarbonylamino; alkylcarbonyloxy; carboxy;aminosulfonyl; alkylsulfonylamino; and alkoxycarbonyl.
 95. The method ofclaim 94, wherein said compound is2-amino-3-[7-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,2-amino-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,2-amino-N-(2-hydroxyethyl)-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide,2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid,2-methanesulfonylamino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide,2-tert-butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionicacid, 2-amino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,2-tert-butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionicacid ethyl ester, 2-nitro-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionicacid ethyl ester,5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,4-{[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one,2-amino-3-[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol,2-(1-(4-phenoxyphenyl)-1H-indol-3-yl)ethanamine,5-{4-[3-(1,2-dihydroxyethyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)-benzonitrile,5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,5-{4-[3-(2-ethoxyoxalyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)-benzonitrile,2-nitro-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,2-amino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,2-nitro-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,2-amino-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,2-nitro-3-[1-(4-phenoxyphenyl)-1H0indol-3-yl]propionic acid ethyl ester,2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}benzonitrile,(S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,(R)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,(S)-5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,(S)-4-{[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one,(S)-2-amino-3-[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol,(S)-5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,(S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}benzonitrile,2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-oxoacetamide,2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,methyl3-(2-amino-1-hydroxy-2-oxoethyl)-1-(4-(3-cyano-4-(trifluoromethyl)-phenoxy)phenyl)-1H-indole-3-carboxylate,2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-oxoacetamide,2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-hydroxyacetamide,3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H-indole-1,3-diyl)bis(propane-1,2-diol),4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-N-methylbenzenesulfonamide,4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-benzenesulfonamide,2-(1-(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2-oxoaceticacid,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carbonitrile,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-5-carbonitrile,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-7-carbonitrile,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carbonitrile,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxamide,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carboxamide,3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxylicacid,5-(4-(4-(1,2-dihydroxyethyl)-3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,(N)-(2-hydroxyethyl)-1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,N-hydroxy-1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,5-fluoro-1-(4-(4-trifluoromethyl)phenoxy)phenyl)-1H-indazole-3-carboxamide,1-(4-(3-cyano-(4-trifluoromethyl)phenoxy)phenyl)-1H-indazole-3-carboxamide,1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indazole-3-carboxamide,1-(4-(4-cyanophenoxy)phenyl)-N-(2,3-dihydroxypropyl)-1H-indazole-3-carboxamide,(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methanol,1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol,3-(1-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol,4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenoxy)benzonitrile,2-(1-(2-diethylamino)ethyl-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)-2-oxoacetamide,2-(1-(2-(diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,3-(1-(2-diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,2-(3-(2,3-dihydroxypropyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide,2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanamide,2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,2-hydroxy-2-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)acetamide,2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol,3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol,(S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-oxoacetamide,2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N—((S)-2,3-dihydroxypropyl)-2-hydroxyacetamide,(2S,2′S)-3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H-indole-1,3-diyl)bis(propane-1,2-diol),(S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,(R)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,(S)-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,(S)-3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,(S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-N-methylbenzenesulfonamide,(S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-benzenesulfonamide,(R)-2-(1-(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2-oxoaceticacid,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carbonitrile,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-5-carbonitrile,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-7-carbonitrile,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carbonitrile,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxamide,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carboxamide,(S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxylicacid,5-(4-(4-(1,2-dihydroxyethyl)-3-((R)-2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,5-(4-(4-(1,2-dihydroxyethyl)-3-((S)-2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,(R)-1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol,(S)-3-(1-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol,(S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenoxy)benzonitrile,(S)-3-(1-(2-diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,(S)-2-(3-(2,3-dihydroxypropyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide,(S)-2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol,(S)-3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol,(S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,(R)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,or a pharmaceutically acceptable salt, prodrug or solvate thereof.